Prospects for neural stem cell-based therapies for neurological diseases.

PubMed

Imitola, Jaime

2007-10-01

Neural stem and progenitor cells have great potential for the treatment of neurological disorders. However, many obstacles remain to translate this field to the patient's bedside, including rationales for using neural stem cells in individual neurological disorders; the challenges of neural stem cell biology; and the caveats of current strategies of isolation and culturing neural precursors. Addressing these challenges is critical for the translation of neural stem cell biology to the clinic. Recent work using neural stem cells has yielded novel biologic concepts such as the importance of the reciprocal interaction between neural stem cells and the neurodegenerative environment. The prospect of using transplants of neural stem cells and progenitors to treat neurological diseases requires a better understanding of the molecular mechanisms of both neural stem cell behavior in experimental models and the intrinsic repair capacity of the injured brain.

Biological restoration of central nervous system architecture and function: part 3-stem cell- and cell-based applications and realities in the biological management of central nervous system disorders: traumatic, vascular, and epilepsy disorders.

PubMed

Farin, Azadeh; Liu, Charles Y; Langmoen, Iver A; Apuzzo, Michael L J

2009-11-01

STEM CELL THERAPY has emerged as a promising novel therapeutic endeavor for traumatic brain injury, spinal cord injury, stroke, and epilepsy in experimental studies. A few preliminary clinical trials have further supported its safety and early efficacy after transplantation into humans. Although not yet clinically available for central nervous system disorders, stem cell technology is expected to evolve into one of the most powerful tools in the biological management of complex central nervous system disorders, many of which currently have limited treatment modalities. The identification of stem cells, discovery of neurogenesis, and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion of the neurosurgeon's capabilities into the neurorestoration and neuroregeneration realms. In Part 3 of a 5-part series on stem cells, we discuss the theory, experimental evidence, and clinical data pertaining to the use of stem cells for the treatment of traumatic, vascular, and epileptic disorders.

Dynamics of change of lipid and monoamine metabolisms and the blood coagulation system during experimental atherosclerosis caused by restriction of movement

NASA Technical Reports Server (NTRS)

Gvishiani, G. S.; Kobakhidze, N. G.

1980-01-01

Shifts in lipid, catecholamine, and blood coagulation systems following various periods (1, 2, 3, and 4 months) of experimentally induced atherosclerosis were studied. The same indices were studied in the tissues of the myocardium, liver, and brain stem-reticular formation after decapitation of the animals at the end of the experiment. Periodic motion restriction caused an increase in blood beta-lipoproteins in the rabbits at the beginning of the experiment. An increase in general cholesterol content and a decrease in the lecithincholesterol index were established at the end of the experiment. Myocardial beta-lipoprotein and brain stem reticular formation general cholesterol contents were elevated; catecholamine content was increased at the end of the experiment. In the initial months, free adrenaline basically increased, while in later months blood adrenaline decreased and blood noradrenaline increased.

In vivo imaging of endogenous neural stem cells in the adult brain

PubMed Central

Rueger, Maria Adele; Schroeter, Michael

2015-01-01

The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their ability to self-renew and differentiate into functional neurons, astrocytes and oligodendrocytes has raised the hope for novel therapies of neurological diseases. Experimentally, those eNSCs can be mobilized in vivo, enhancing regeneration and accelerating functional recovery after, e.g., focal cerebral ischemia, thus constituting a most promising approach in stem cell research. In order to translate those current experimental approaches into a clinical setting in the future, non-invasive imaging methods are required to monitor eNSC activation in a longitudinal and intra-individual manner. As yet, imaging protocols to assess eNSC mobilization non-invasively in the live brain remain scarce, but considerable progress has been made in this field in recent years. This review summarizes and discusses the current imaging modalities suitable to monitor eNSCs in individual experimental animals over time, including optical imaging, magnetic resonance tomography and-spectroscopy, as well as positron emission tomography (PET). Special emphasis is put on the potential of each imaging method for a possible clinical translation, and on the specificity of the signal obtained. PET-imaging with the radiotracer 3’-deoxy-3’-[18F]fluoro-L-thymidine in particular constitutes a modality with excellent potential for clinical translation but low specificity; however, concomitant imaging of neuroinflammation is feasible and increases its specificity. The non-invasive imaging strategies presented here allow for the exploitation of novel treatment strategies based upon the regenerative potential of eNSCs, and will help to facilitate a translation into the clinical setting. PMID:25621107

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

PubMed

Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

2005-01-01

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Estimation of the brain stem volume by stereological method on magnetic resonance imaging.

PubMed

Erbagci, Hulya; Keser, Munevver; Kervancioglu, Selim; Kizilkan, Nese

2012-11-01

Neuron loss that occurs in some neurodegenerative diseases can lead to volume alterations by causing atrophy in the brain stem. The aim of this study was to determine the brain stem volume and the volume ratio of the brain stem to total brain volume related to gender and age using new Stereo Investigator system in normal subjects. For this purpose, MR images of 72 individuals who have no pathologic condition were evaluated. The total brain volumes of female and male were calculated as 966.81 ± 77.44 and 1,074.06 ± 111.75 cm3, respectively. Brain stem volumes of female and male were determined as 18.99 ± 2.36 and 22.05 ± 4.01 cm3, respectively. The ratios of brain stem volume to total brain volume were 1.96 ± 0.17 in female and 2.05 ± 0.29 in male. The total brain and brain stem volumes were observed smaller in female and it is statistically significant. Among the individuals whose ages are between 20 and 40, total brain and brain stem volume measurements with aging were not statistically significant. As a result, we believe that the measurement of brain stem volume with an objective and efficient calculation method will contribute to the early diagnosis of neurodegenerative diseases, as well as to determine the rate of disease progression, and the outcomes of treatment.

Hypertensive brain stem encephalopathy.

PubMed

Liao, Pen-Yuan; Lee, Chien-Chang; Chen, Cheng-Yu

2015-01-01

A 48-year-old man presented with headache and extreme hypertension. Computed tomography showed diffuse brain stem hypodensity. Magnetic resonance imaging revealed diffuse brain stem vasogenic edema. Hypertensive brain stem encephalopathy is an uncommon manifestation of hypertensive encephalopathy, which classically occurs at parietooccipital white matter. Because of its atypical location, the diagnosis can be challenging. Moreover, the coexistence of hypertension and brain stem edema could also direct clinicians toward a diagnosis of ischemic infarction, leading to a completely contradictory treatment goal.

Intrinsic epidermoid of the brain stem: case report and review of the literature.

PubMed

Singh, Saraj K; Jain, Kapil; Jain, Vijendra Kumar

2018-03-19

Purely cystic brain stem epidermoid is a rare diagnosis among all brainstem cystic lesions. Further, it is very rare in pediatric age group. Here, we are reporting a rare case of completely cystic brain stem epidermoid in a child. The patient presented with clinical features of brain stem involvement. MRI brain was suggestive of cystic brain stem lesion. Patient went through surgical procedure. Final diagnosis of epidermoid cyst was confirmed on histopathological report. With the help of various advanced sequences of MRI like diffusion and ADC, diagnosis of epidermoid cyst can be established at unusual intracranial site also. Surgical resection of epidermoid cyst at brain stem should be attempted judiciously utilizing all modern tools of neurosurgery.

Age-dependent acute interference with stem and progenitor cell proliferation in the hippocampus after exposure to 1800 MHz electromagnetic radiation.

PubMed

Xu, Falin; Bai, Qiongdan; Zhou, Kai; Ma, Li; Duan, Jiajia; Zhuang, Fangli; Xie, Cuicui; Li, Wenli; Zou, Peng; Zhu, Changlian

2017-01-01

To investigate the effects of exposure to an 1800 MHz electromagnetic field on cell death and cell proliferation in the developing brain, postnatal day 7 (P7) and P21 healthy Kunming mice were randomly assigned into the experimental and control groups. The experimental groups were exposed to an 1800 MHz electromagnetic field for 8 h daily for three consecutive days. The thymidine analog 5-bromo-2-deoxyuridine (BrdU) was injected intraperitoneally 1 h before each exposure session, and all animals were sacrificed 24 h after the last exposure. Cell death and proliferation markers were detected by immunohistochemistry in the dentate gyrus of the hippocampus. Electromagnetic exposure has no influence on cell death in the dentate gyrus of the hippocampus in P7 and P21 mice as indicated by active caspase-3 immunostaining and Fluoro-Jade labeling. The basal cell proliferation in the hippocampus was higher in P7 than in P21 mice as indicated by the number of cells labeled with BrdU and by immunohistochemical staining for phosphor-histone H3 (PHH3) and brain lipid-binding protein (BLBP). Electromagnetic exposure stimulated DNA synthesis in P7 neural stem and progenitor cells, but reduced cell division and the total number of stem cells in the hippocampus as indicated by increased BrdU labeling and reduced PHH3 and BLBP labeling compared to P7 control mice. There were no significant changes in cell proliferation in P21 mice after exposure to the electromagnetic field. These results indicate that interference with stem cell proliferation upon short-term exposure to an 1800 MHz electromagnetic field depends on the developmental stage of the brain.

Aberrant brain stem morphometry associated with sleep disturbance in drug-naïve subjects with Alzheimer's disease.

PubMed

Lee, Ji Han; Jung, Won Sang; Choi, Woo Hee; Lim, Hyun Kook

2016-01-01

Among patients with Alzheimer's disease (AD), sleep disturbances are common and serious noncognitive symptoms. Previous studies of AD patients have identified deformations in the brain stem, which may play an important role in the regulation of sleep. The aim of this study was to further investigate the relationship between sleep disturbances and alterations in brain stem morphology in AD. In 44 patients with AD and 40 healthy elderly controls, sleep disturbances were measured using the Neuropsychiatry Inventory sleep subscale. We employed magnetic resonance imaging-based automated segmentation tools to examine the relationship between sleep disturbances and changes in brain stem morphology. Analyses of the data from AD subjects revealed significant correlations between the Neuropsychiatry Inventory sleep-subscale scores and structural alterations in the left posterior lateral region of the brain stem, as well as normalized brain stem volumes. In addition, significant group differences in posterior brain stem morphology were observed between the AD group and the control group. This study is the first to analyze an association between sleep disturbances and brain stem morphology in AD. In line with previous findings, this study lends support to the possibility that brain stem structural abnormalities might be important neurobiological mechanisms underlying sleep disturbances associated with AD. Further longitudinal research is needed to confirm these findings.

Curcumin: a promising agent targeting cancer stem cells.

PubMed

Zang, Shufei; Liu, Tao; Shi, Junping; Qiao, Liang

2014-01-01

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.

Signals that regulate the oncogenic fate of neural stem cells and progenitors

PubMed Central

Swartling, Fredrik J.; Bolin, Sara; Phillips, Joanna J.; Persson, Anders I.

2013-01-01

Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors. PMID:23376224

The Potential of Stem Cells in Treatment of Traumatic Brain Injury.

PubMed

Weston, Nicole M; Sun, Dong

2018-01-25

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rate after TBI, treatment is lacking for brain functional recovery and structural repair in clinic. Recent studies have suggested that the mature brain harbors neural stem cells which have regenerative capacity following brain insults. Much progress has been made in preclinical TBI model studies in understanding the behaviors, functions, and regulatory mechanisms of neural stem cells in the injured brain. Different strategies targeting these cell population have been assessed in TBI models. In parallel, cell transplantation strategy using a wide range of stem cells has been explored for TBI treatment in pre-clinical studies and some in clinical trials. This review summarized strategies which have been explored to enhance endogenous neural stem cell-mediated regeneration and recent development in cell transplantation studies for post-TBI brain repair. Thus far, neural regeneration through neural stem cells either by modulating endogenous neural stem cells or by stem cell transplantation has attracted much attention. It is highly speculated that targeting neural stem cells could be a potential strategy to repair and regenerate the injured brain. Neuroprotection and neuroregeneration are major aspects for TBI therapeutic development. With technique advancement, it is hoped that stem cell-based therapy targeting neuroregeneration will be able to translate to clinic in not so far future.

Dorsal brain stem syndrome: MR imaging location of brain stem tegmental lesions in neonates with oral motor dysfunction.

PubMed

Quattrocchi, C C; Longo, D; Delfino, L N; Cilio, M R; Piersigilli, F; Capua, M D; Seganti, G; Danhaive, O; Fariello, G

2010-09-01

The anatomic extent of brain stem damage may provide information about clinical outcome and prognosis in children with hypoxic-ischemic encephalopathy and oral motor dysfunction. The aim of this study was to retrospectively characterize the location and extent of brain stem lesions in children with oral motor dysfunction. From January 2005 to August 2009, 43 infants hospitalized at our institution were included in the study because of a history of hypoxic-ischemic events. Of this group, 14 patients showed oral motor dysfunction and brain stem tegmental lesions detected at MR imaging. MR imaging showed hypoxic-ischemic lesions in supra- and infratentorial areas. Six of 14 patients revealed only infratentorial lesions. Focal symmetric lesions of the tegmental brain stem were always present. The lesions appeared hyperintense on T2-weighted images and hypointense on IR images. We found a strong association (P < .0001) between oral motor dysfunction and infratentorial lesions on MR imaging. Oral motor dysfunction was associated with brain stem tegmental lesions in posthypoxic-ischemic infants. The MR imaging examination should be directed to the brain stem, especially when a condition of prolonged gavage feeding is necessary in infants.

How Stem Cells Speak with Host Immune Cells in Inflammatory Brain Diseases

PubMed Central

Pluchino, Stefano; Cossetti, Chiara

2014-01-01

Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases. PMID:23633288

Are there endogenous stem cells in the spinal cord?

PubMed

Ferrucci, Michela; Ryskalin, Larisa; Busceti, Carla L; Gaglione, Anderson; Biagioni, Francesca; Fornai, Francesco

2017-12-01

Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.

Posterior brain in fetuses with open spina bifida at 11 to 13 weeks.

PubMed

Lachmann, Robert; Chaoui, Rabih; Moratalla, Jose; Picciarelli, Gemma; Nicolaides, Kypros H

2011-01-01

To measure the changes in the posterior fossa in first-trimester fetuses with open spina bifida (OSB). The brain stem diameter and brain stem to occipital bone (BSOB) diameter were measured in stored images of the mid-sagittal view of the fetal face at 11(+0) to 13(+6) weeks from 30 fetuses with OSB and 1000 normal controls. In the control group, the brain stem and BSOB diameter increased significantly with crown-rump length (CRL) and the brain stem to BSOB ratio decreased. In the spina bifida group, the brain stem diameter was above the 95th percentile of the control group in 29 (96.7%) cases, the BSOB diameter was below the 5th percentile in 26 (86.7%) and the brain stem to BSOB ratio was above the 95th percentile in all cases. At 11 to 13 weeks the majority of fetuses with OSB have measurable abnormalities in the posterior brain.

Isolated brain stem edema in a pediatric patient with head trauma: a case report.

PubMed

Basarslan, K; Basarslan, F; Karakus, A; Yilmaz, C

2015-01-01

Brain stem is the most vital part of our body and is a transitional region of the brain that connects the cerebrum with the spinal cord. Though, being small in size, it is full of indispensible functions such as the breathing, heart beat. Injury to the brain stem has similar effects as a brain injury, but it is more fatal. Use of the Glasgow Coma Score as a prognostic indicator of outcome in patients with head injuries is widely accepted in clinical practice. Traumatic brain stem edema in children is rare, but is associated with poor outcome. The question is that whether it is being aware of computerized tomography appearance of the posterior fossa when initial evaluating pediatric patients with head trauma at emergency clinics. Normal and edematous brain stem without an additional pathology are slightly different and not distinguished easily. On the other hand, brain stem edema should be promptly identified and appropriately treated in a short time.

Electrical Guidance of Human Stem Cells in the Rat Brain.

PubMed

Feng, Jun-Feng; Liu, Jing; Zhang, Lei; Jiang, Ji-Yao; Russell, Michael; Lyeth, Bruce G; Nolta, Jan A; Zhao, Min

2017-07-11

Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Combination cell therapy with mesenchymal stem cells and neural stem cells for brain stroke in rats.

PubMed

Hosseini, Seyed Mojtaba; Farahmandnia, Mohammad; Razi, Zahra; Delavari, Somayeh; Shakibajahromi, Benafsheh; Sarvestani, Fatemeh Sabet; Kazemi, Sepehr; Semsar, Maryam

2015-05-01

Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke. The Mesenchymal stem cells were isolated from adult rat bone marrow and the neural stem cells were isolated from ganglion eminence of rat embryo 14 days. The Mesenchymal stem cells were injected 1 day after middle cerebral artery occlusion (MCAO) and the neural stem cells transplanted 7 day after MCAO. After 28 days, the neurological outcomes and brain lesion volumes were evaluated. Also, the activity of Caspase 3 was assessed in different groups. The group which received combination cell therapy had better neurological examination and less brain lesion. Also the combination cell therapy group had the least Caspase 3 activity among the groups. The combination cell therapy is more effective than Mesenchymal stem cell therapy and neural stem cell therapy separately in treating the brain stroke in rats.

The use of stem cells in regenerative medicine for Parkinson's and Huntington's Diseases.

PubMed

Lescaudron, L; Naveilhan, P; Neveu, I

2012-01-01

Cell transplantation has been proposed as a means of replacing specific cell populations lost through neurodegenerative processes such as that seen in Parkinson's or Huntington's diseases. Improvement of the clinical symptoms has been observed in a number of Parkinson and Huntington's patients transplanted with freshly isolated fetal brain tissue but such restorative approach is greatly hampered by logistic and ethical concerns relative to the use of fetal tissue, in addition to potential side effects that remain to be controlled. In this context, stem cells that are capable of self-renewal and can differentiate into neurons, have received a great deal of interest, as demonstrated by the numerous studies based on the transplantation of neural stem/progenitor cells, embryonic stem cells or mesenchymal stem cells into animal models of Parkinson's or Huntington's diseases. More recently, the induction of pluripotent stem cells from somatic adult cells has raised a new hope for the treatment of neurodegenerative diseases. In the present article, we review the main experimental approaches to assess the efficiency of cell-based therapy for Parkinson's or Huntington's diseases, and discuss the recent advances in using stem cells to replace lost dopaminergic mesencephalic or striatal neurons. Characteristics of the different stem cells are extensively examined with a special attention to their ability of producing neurotrophic or immunosuppressive factors, as these may provide a favourable environment for brain tissue repair and long-term survival of transplanted cells in the central nervous system. Thus, stem cell therapy can be a valuable tool in regenerative medicine.

Magnetic resonance imaging of the kinked fetal brain stem: a sign of severe dysgenesis.

PubMed

Stroustrup Smith, Annemarie; Levine, Deborah; Barnes, Patrick D; Robertson, Richard L

2005-12-01

Magnetic resonance imaging (MRI) allows visualization of the fetal brain stem in a manner not previously possible. A "kinked" brain stem is a sign of severe neurodysgenesis. The purpose of this series was to describe cases of a kinked brain stem detected on prenatal MRI and to discuss the possible genetic and syndromic etiologies. Seven cases of a kinked brain stem on fetal MRI (gestational age range, 18-34 weeks) were reviewed and correlated with other clinical, genetic, imaging, and autopsy findings. In all cases, there was associated cerebellar hypogenesis. Additional findings were ventriculomegaly (4 cases), cerebral hypogenesis (3 cases), microcephaly (4 cases), schizencephaly (1 case), cephalocele (1 case), hypogenesis of the corpus callosum (1 case), and hydrocephalus (1 case). In 2 cases, prenatal sonography misidentified the kinked brain stem as the cerebellum. A kinked brain stem is an indicator of severe neurodysgenesis arising early in gestation. Magnetic resonance imaging provides the necessary resolution to detect this sign and delineate any associated anomalies in utero to assist with further genetic evaluation, management, and counseling.

Semiautomated volumetry of the cerebrum, cerebellum-brain stem, and temporal lobe on brain magnetic resonance images.

PubMed

Hayashi, Norio; Sanada, Shigeru; Suzuki, Masayuki; Matsuura, Yukihiro; Kawahara, Kazuhiro; Tsujii, Hideo; Yamamoto, Tomoyuki; Matsui, Osamu

2008-02-01

The aim of this study was to develop an automated method of segmenting the cerebrum, cerebellum-brain stem, and temporal lobe simultaneously on magnetic resonance (MR) images. We obtained T1-weighted MR images from 10 normal subjects and 19 patients with brain atrophy. To perform automated volumetry from MR images, we performed the following three steps: (1) segmentation of the brain region; (2) separation between the cerebrum and the cerebellum-brain stem; and (3) segmentation of the temporal lobe. Evaluation was based on the correctly recognized region (CRR) (i.e., the region recognized by both the automated and manual methods). The mean CRRs of the normal and atrophic brains were 98.2% and 97.9% for the cerebrum, 87.9% and 88.5% for the cerebellum-brain stem, and 76.9% and 85.8% for the temporal lobe, respectively. We introduce an automated volumetric method for the cerebrum, cerebellum-brain stem, and temporal lobe on brain MR images. Our method can be applied to not only the normal brain but also the atrophic brain.

MRI patterns in prolonged low response states following traumatic brain injury in children and adolescents.

PubMed

Patrick, Peter D; Mabry, Jennifer L; Gurka, Matthew J; Buck, Marcia L; Boatwright, Evelyn; Blackman, James A

2007-01-01

To explore the relationship between location and pattern of brain injury identified on MRI and prolonged low response state in children post-traumatic brain injury (TBI). This observational study compared 15 children who spontaneously recovered within 30 days post-TBI to 17 who remained in a prolonged low response state. 92.9% of children with brain stem injury were in the low response group. The predicted probability was 0.81 for brain stem injury alone, increasing to 0.95 with a regional pattern of injury to the brain stem, basal ganglia, and thalamus. Low response state in children post-TBI is strongly correlated with two distinctive regions of injury: the brain stem alone, and an injury pattern to the brain stem, basal ganglia, and thalamus. This study demonstrates the need for large-scale clinical studies using MRI as a tool for outcome assessment in children and adolescents following severe TBI.

Childhood Brain Stem Glioma Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood brain stem glioma treatment options can include surgery, radiation therapy, chemotherapy, cerebral spinal fluid diversion, observation, and targeted therapy. Learn more about newly diagnosed and recurrent childhood brain stem glioma in this expert-reviewed summary.

[Brainstem auditory evoked potentials in neurophysiological assessment of brain stem dysfunction in patients with atherostenosis of vertebral arteries].

PubMed

Maksimova, M Yu; Sermagambetova, Zh N; Skrylev, S I; Fedin, P A; Koshcheev, A Yu; Shchipakin, V L; Sinicyn, I A

To assess brain stem dysfunction in patients with hemodynamically significant stenosis of vertebral arteries (VA) using short latency brainstem auditory evoked potentials (BAEP). The study group included 50 patients (mean age 64±6 years) with hemodynamically significant extracranial VA stenosis. Patients with hemodynamically significant extracranial VA stenosis had BAEP abnormalities including the elongation of interpeak intervals I-V and peak V latency as well as the reduction of peak I amplitude. After transluminal balloon angioplasty with stenting of VA stenoses, there was a shortening of peak V latency compared to the preoperative period that reflected the improvement of brain stem conductive functions. Atherostenosis of vertebral arteries is characterized by the signs of brain stem dysfunction, predominantly in the pontomesencephal brain stem. After transluminal balloon angioplasty with stenting of VA, the improvement of brain stem conductive functions was observed.

Intravenous administration of bone marrow-derived mesenchymal stem cells induces a switch from classical to atypical symptoms in experimental autoimmune encephalomyelitis.

PubMed

Kurte, Mónica; Bravo-Alegría, Javiera; Torres, Alexander; Carrasco, Vania; Ibáñez, Cristina; Vega-Letter, Ana María; Fernández-O'Ryan, Catalina; Irarrázabal, Carlos E; Figueroa, Fernando E; Fuentealba, Rodrigo A; Riedel, Claudia; Carrión, Flavio

2015-01-01

Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis.

Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cells Induces a Switch from Classical to Atypical Symptoms in Experimental Autoimmune Encephalomyelitis

PubMed Central

Kurte, Mónica; Bravo-Alegría, Javiera; Torres, Alexander; Carrasco, Vania; Ibáñez, Cristina; Vega-Letter, Ana María; Fernández-O'Ryan, Catalina; Irarrázabal, Carlos E.; Figueroa, Fernando E.; Fuentealba, Rodrigo A.; Riedel, Claudia; Carrión, Flavio

2015-01-01

Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis. PMID:25838828

Can adult neural stem cells create new brains? Plasticity in the adult mammalian neurogenic niches: realities and expectations in the era of regenerative biology.

PubMed

Kazanis, Ilias

2012-02-01

Since the first experimental reports showing the persistence of neurogenic activity in the adult mammalian brain, this field of neurosciences has expanded significantly. It is now widely accepted that neural stem and precursor cells survive during adulthood and are able to respond to various endogenous and exogenous cues by altering their proliferation and differentiation activity. Nevertheless, the pathway to therapeutic applications still seems to be long. This review attempts to summarize and revisit the available data regarding the plasticity potential of adult neural stem cells and of their normal microenvironment, the neurogenic niche. Recent data have demonstrated that adult neural stem cells retain a high level of pluripotency and that adult neurogenic systems can switch the balance between neurogenesis and gliogenesis and can generate a range of cell types with an efficiency that was not initially expected. Moreover, adult neural stem and precursor cells seem to be able to self-regulate their interaction with the microenvironment and even to contribute to its synthesis, altogether revealing a high level of plasticity potential. The next important step will be to elucidate the factors that limit this plasticity in vivo, and such a restrictive role for the microenvironment is discussed in more details.

Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells

PubMed Central

Spéder, Pauline; Brand, Andrea H.

2014-01-01

Summary Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion. PMID:25065772

MRI-Based Measurement of Brain Stem Cross-Sectional Area in Relapsing-Remitting Multiple Sclerosis.

PubMed

Chivers, Tomos R; Constantinescu, Cris S; Tench, Christopher R

2015-01-01

To determine if patients with relapsing-remitting multiple sclerosis (RRMS) have a reduced brain stem cross-sectional area (CSA) compared to age- and sex-matched controls. The brain stem is a common site of involvement in MS. However, relatively few imaging studies have investigated brain stem atrophy. Brain magnetic resonance imaging (MRI) was performed on patients and controls using a 1.5T MRI scanner with a quadrature head coil. Three-dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images with 128 contiguous slices, covering the whole brain and brain stem and a T2-weighted image with 3 mm transverse contiguous images were acquired. We measured the brain stem CSA at three sites, the midbrain, the pons, and the medulla oblongata in 35 RRMS patients and 35 controls using a semiautomated algorithm. CSA readings were normalized using the total external cranial volume to reduce normal population variance and increase statistical power. A significant CSA reduction was found in the midbrain (P ≤ .001), pons (P ≤ .001), and the medulla oblongata (P = .047) postnormalization. A CSA reduction of 9.3% was found in the midbrain, 8.7% in the pons, and 6.5% in the medulla oblongata. A significantly reduced, normalized brain stem CSA was detected in all areas of the brain stem of the RRMS patients, when compared to age- and gender-matched controls. Lack of detectable upper cervical cord atrophy in the same patients suggests some independence of the MS pathology in these regions. Copyright © 2015 by the American Society of Neuroimaging.

Training stem cells for treatment of malignant brain tumors

PubMed Central

Li, Shengwen Calvin; Kabeer, Mustafa H; Vu, Long T; Keschrumrus, Vic; Yin, Hong Zhen; Dethlefs, Brent A; Zhong, Jiang F; Weiss, John H; Loudon, William G

2014-01-01

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for patients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution (i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system. PMID:25258664

Neural cells derived from adult bone marrow and umbilical cord blood.

PubMed

Sanchez-Ramos, Juan R

2002-09-15

Under experimental conditions, tissue-specific stem cells have been shown to give rise to cell lineages not normally found in the organ or tissue of residence. Neural stem cells from fetal brain have been shown to give rise to blood cell lines and conversely, bone marrow stromal cells have been reported to generate skeletal and cardiac muscle, oval hepatocytes, as well as glia and neuron-like cells. This article reviews studies in which cells from postnatal bone marrow or umbilical cord blood were induced to proliferate and differentiate into glia and neurons, cellular lineages that are not their normal destiny. The review encompasses in vitro and in vivo studies with focus on experimental variables, such as the source and characterization of cells, cell-tracking methods, and markers of neural differentiation. The existence of stem/progenitor cells with previously unappreciated proliferation and differentiation potential in postnatal bone marrow and in umbilical cord blood opens up the possibility of using stem cells found in these tissues to treat degenerative, post-traumatic and hereditary diseases of the central nervous system. Copyright 2002 Wiley-Liss, Inc.

IDH1 Mutation in Brain Stem Glioma: Case Report and Review of Literature.

PubMed

Javadi, Seyed Amirhossein; Hartmann, Christian; Walter, Gerhard Franz; Banan, Roozbeh; Samii, Amir

2018-01-01

The role of isocitrate dehydrogenase 1 (IDH1) mutation in brain stem glioma is not clear. To the best of our knowledge, six cases of brain stem gliomas carrying IDH1/2 mutations are currently reported in the literature. One case of diffuse brain stem glioma with IDH1 mutation, which was followed for 2 years, is presented and compared with IDH1 negative tumors. A 22-year-old lady was referred with diplopia and left arm palsy. Neuroimaging detected a nonenhancing, nonhomogeneous diffuse infiltrating brain stem tumor extending from pons to medulla. Microsurgical debulking was performed. Microscopic evaluation of the tissue specimen and immunohistochemistry revealed an astrocytoma WHO Grade II with proliferation rate of 3% and glial fibrillary acidic protein (GFAP)-positive tumor cells. Interestingly, the tumor cells expressed mutated IDH1 R132H protein. The patient underwent adjuvant radiation and chemotherapy. The primary and 2 years' clinical/radiological characteristics did not indicate any significant difference from other cases without IDH1 mutation. the prognostic value of IDH1/2 mutation in brain stem glioma is unclear. Brain stem biopsies may allow determination of a tissue-based tumor diagnosis for further investigations.

Volumetric evaluation of the relations among the cerebrum, cerebellum and brain stem in young subjects: a combination of stereology and magnetic resonance imaging.

PubMed

Ekinci, Nihat; Acer, Niyazi; Akkaya, Akcan; Sankur, Seref; Kabadayi, Taner; Sahin, Bünyamin

2008-08-01

The Cavalieri estimator using a point grid is used to estimate the volume of three-dimensional structures based on two-dimensional slices of the object. The size of the components of intracranial neural structures should have proportional relations among them. The volume fraction approach of stereological methods provides information about volumetric relations of the components of structures. The purpose of our study is to estimate the volume and volume fraction data related to the cerebrum, cerebellum and brain stem. In this study, volume of the total brain, cerebrum, cerebellum and brain stem were estimated in 24 young Turkish volunteers (12 males and 12 females) who are free of any neurological symptoms and signs. The volume and volume fraction of the total brain, cerebrum, cerebellum and brain stem were determined on magnetic resonance (MR) images using the point-counting approach of stereological methods. The mean (+/-SD) total brain, cerebrum and cerebellum volumes were 1,202.05 +/- 103.51, 1,143.65 +/- 106.25 cm3 in males and females, 1,060.0 +/- 94.6, 1,008.9 +/- 104.3 cm3 in males and females, 117.75 +/- 10.7, 111.83 +/- 8.0 cm3 in males and females, respectively. The mean brain stem volumes were 24.3 +/- 2.89, 22.9 +/- 4.49 cm3 in males and females, respectively. Our results revealed that female subjects have less cerebral, cerebellar and brain stem volumes compared to males, although there was no statistically significant difference between genders (P > 0.05). The volume ratio of the cerebrum to total brain volume (TBV), cerebellum to TBV and brain stem to TBV were 88.16 and 88.13% in males and females, 9.8 and 9.8% in males and females, 2.03 and 2.03% in males and females, respectively. The volume ratio of the cerebellum to cerebrum, brain stem to cerebrum and brain stem to cerebellum were 11.12 and 11.16% in males and females, 2.30 and 2.31% in males and females, 20.7 and 20.6% in males and females, respectively. The difference between the genders was not statistically significant (P > 0.05). Our results revealed that the volumetric composition of the cerebrum, cerebellum and brain stem does not show sexual dimorphism.

Expansion of Multipotent Stem Cells from the Adult Human Brain

PubMed Central

Murrell, Wayne; Palmero, Emily; Bianco, John; Stangeland, Biljana; Joel, Mrinal; Paulson, Linda; Thiede, Bernd; Grieg, Zanina; Ramsnes, Ingunn; Skjellegrind, Håvard K.; Nygård, Ståle; Brandal, Petter; Sandberg, Cecilie; Vik-Mo, Einar; Palmero, Sheryl; Langmoen, Iver A.

2013-01-01

The discovery of stem cells in the adult human brain has revealed new possible scenarios for treatment of the sick or injured brain. Both clinical use of and preclinical research on human adult neural stem cells have, however, been seriously hampered by the fact that it has been impossible to passage these cells more than a very few times and with little expansion of cell numbers. Having explored a number of alternative culturing conditions we here present an efficient method for the establishment and propagation of human brain stem cells from whatever brain tissue samples we have tried. We describe virtually unlimited expansion of an authentic stem cell phenotype. Pluripotency proteins Sox2 and Oct4 are expressed without artificial induction. For the first time multipotency of adult human brain-derived stem cells is demonstrated beyond tissue boundaries. We characterize these cells in detail in vitro including microarray and proteomic approaches. Whilst clarification of these cells’ behavior is ongoing, results so far portend well for the future repair of tissues by transplantation of an adult patient’s own-derived stem cells. PMID:23967194

Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse.

PubMed

Jean-Xavier, Céline; Perreault, Marie-Claude

2018-01-01

The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs) during drug-induced fictive locomotor-like activity (LLA) in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC) and hindlimb MNs in lateral motor column (LMC). The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor.

Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse

PubMed Central

Jean-Xavier, Céline; Perreault, Marie-Claude

2018-01-01

The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs) during drug-induced fictive locomotor-like activity (LLA) in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC) and hindlimb MNs in lateral motor column (LMC). The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor. PMID:29479302

Osthole Enhances the Therapeutic Efficiency of Stem Cell Transplantation in Neuroendoscopy Caused Traumatic Brain Injury.

PubMed

Tao, Zhen-Yu; Gao, Peng; Yan, Yu-Hui; Li, Hong-Yan; Song, Jie; Yang, Jing-Xian

2017-01-01

Neuroendoscopy processes can cause severe traumatic brain injury. Existing therapeutic methods, such as neural stem cell transplantation and osthole have not been proven effective. Therefore, there is an emerging need on the development of new techniques for the treatment of brain injuries. In this study we propose to combine the above stem cell based methods and then evaluate the efficiency and accuracy of the new method. Mice were randomly divided into four groups: group 1 (brain injury alone); group 2 (osthole); group 3 (stem cell transplantation); and group 4 (osthole combined with stem cell transplantation). We carried out water maze task to exam spatial memory. Immunocytochemistry was used to test the inflammatory condition of each group, and the differentiation of stem cells. To evaluate the condition of the damaged blood brain barrier restore, we detect the Evans blue (EB) extravasation across the blood brain barrier. The result shows that osthole and stem cell transplantation combined therapeutic method has a potent effect on improving the spatial memory. This combined method was more effective on inhibiting inflammation and preventing neuronal degeneration than the single treated ones. In addition, there was a distinct decline of EB extravasation in the combined treatment groups, which was not observed in single treatment groups. Most importantly, the combined usage of osthole and stem cell transplantation provide a better treatment for the traumatic brain injury caused by neuroendoscopy. The collective evidence indicates osthole combined with neural stem cell transplantation is superior than either method alone for the treatment of traumatic brain injury caused by neuroendoscopy.

Isolated brain stem lesion in children: is it acute disseminated encephalomyelitis or not?

PubMed

Alper, G; Sreedher, G; Zuccoli, G

2013-01-01

Isolated brain stem lesions presenting with acute neurologic findings create a major diagnostic dilemma in children. Although the brain stem is frequently involved in ADEM, solitary brain stem lesions are unusual. We performed a retrospective review in 6 children who presented with an inflammatory lesion confined to the brain stem. Two children were diagnosed with connective tissue disorder, CNS lupus, and localized scleroderma. The etiology could not be determined in 1, and clinical features suggested monophasic demyelination in 3. In these 3 children, initial lesions demonstrated vasogenic edema; all showed dramatic response to high-dose corticosteroids and made a full clinical recovery. Follow-up MRI showed complete resolution of lesions, and none had relapses at >2 years of follow-up. In retrospect, these cases are best regarded as a localized form of ADEM. We conclude that though ADEM is typically a disseminated disease with multifocal lesions, it rarely presents with monofocal demyelination confined to the brain stem.

Brainstem death: A comprehensive review in Indian perspective

PubMed Central

Dhanwate, Anant Dattatray

2014-01-01

With the advent of cardiopulmonary resuscitation techniques, the cardiopulmonary definition of death lost its significance in favor of brain death. Brain death is a permanent cessation of all functions of the brain in which though individual organs may function but lack of integrating function of the brain, lack of respiratory drive, consciousness, and cognition confirms to the definition that death is an irreversible cessation of functioning of the organism as a whole. In spite of medical and legal acceptance globally, the concept of brain death and brain-stem death is still unclear to many. Brain death is not promptly declared due to lack of awareness and doubts about the legal procedure of certification. Many brain dead patients are kept on life supporting systems needlessly. In this comprehensive review, an attempt has been made to highlight the history and concept of brain death and brain-stem death; the anatomical and physiological basis of brain-stem death, and criteria to diagnose brain-stem death in India. PMID:25249744

Identity of sensory and motor systems that are critical to the immobility reflex ("animal hypnosis").

PubMed

Klemm, W R

1976-01-01

This review presents an analysis of the sensory and motor mechanisms as they are now understood that cause the immobility reflex (IR). Of the sensory systems that conceivably could trigger and sustain the IR, as commonly induced experimentally by inversion and manual restraint, evidence has been presented to eliminate some senses (vestibular, vision, sound, many visceral sensations, olfaction, taste, temperature), while incriminating tactile and proprioceptive influences. Of the motor systems which could cause the profound immobility during IR, neurosurgical and electrophysiological evidence identifies the locus of the inhibitory neurons in the brain stem and/or spinal cord. The evidence reviewed leads to a unified working hypothesis of IR mechanisms. IR is considered to be caused by a group of neurons in the brain stem which inhibit spinal motoneurons, either directly or indirectly, when those inhibitory neurons are activated by a specific pattern of tactile and proprioceptive input. Modulation of the IR control system appears to come from the limbic system, which under fear-producing conditions, potentiates the IR in part by release of epinephrine. Inhibition of the IR control system appears to come from the neocortex, as well as the brain stem reticulum, when it is activated by nonspecific, arousing somaesthetic sensations that produce generalized activation of the neocortex and skeletal muscle.

Establishment and Characterization of a Tumor Stem Cell-Based Glioblastoma Invasion Model.

PubMed

Jensen, Stine Skov; Meyer, Morten; Petterson, Stine Asferg; Halle, Bo; Rosager, Ann Mari; Aaberg-Jessen, Charlotte; Thomassen, Mads; Burton, Mark; Kruse, Torben A; Kristensen, Bjarne Winther

2016-01-01

Glioblastoma is the most frequent and malignant brain tumor. Recurrence is inevitable and most likely connected to tumor invasion and presence of therapy resistant stem-like tumor cells. The aim was therefore to establish and characterize a three-dimensional in vivo-like in vitro model taking invasion and tumor stemness into account. Glioblastoma stem cell-like containing spheroid (GSS) cultures derived from three different patients were established and characterized. The spheroids were implanted in vitro into rat brain slice cultures grown in stem cell medium and in vivo into brains of immuno-compromised mice. Invasion was followed in the slice cultures by confocal time-lapse microscopy. Using immunohistochemistry, we compared tumor cell invasion as well as expression of proliferation and stem cell markers between the models. We observed a pronounced invasion into brain slice cultures both by confocal time-lapse microscopy and immunohistochemistry. This invasion closely resembled the invasion in vivo. The Ki-67 proliferation indexes in spheroids implanted into brain slices were lower than in free-floating spheroids. The expression of stem cell markers varied between free-floating spheroids, spheroids implanted into brain slices and tumors in vivo. The established invasion model kept in stem cell medium closely mimics tumor cell invasion into the brain in vivo preserving also to some extent the expression of stem cell markers. The model is feasible and robust and we suggest the model as an in vivo-like model with a great potential in glioma studies and drug discovery.

Stem cell recruitment of newly formed host cells via a successful seduction? Filling the gap between neurogenic niche and injured brain site.

PubMed

Tajiri, Naoki; Kaneko, Yuji; Shinozuka, Kazutaka; Ishikawa, Hiroto; Yankee, Ernest; McGrogan, Michael; Case, Casey; Borlongan, Cesar V

2013-01-01

Here, we report that a unique mechanism of action exerted by stem cells in the repair of the traumatically injured brain involves their ability to harness a biobridge between neurogenic niche and injured brain site. This biobridge, visualized immunohistochemically and laser captured, corresponded to an area between the neurogenic subventricular zone and the injured cortex. That the biobridge expressed high levels of extracellular matrix metalloproteinases characterized initially by a stream of transplanted stem cells, but subsequently contained only few to non-detectable grafts and overgrown by newly formed host cells, implicates a novel property of stem cells. The transplanted stem cells manifest themselves as pathways for trafficking the migration of host neurogenic cells, but once this biobridge is formed between the neurogenic site and the injured brain site, the grafted cells disappear and relinquish their task to the host neurogenic cells. Our findings reveal that long-distance migration of host cells from the neurogenic niche to the injured brain site can be achieved through transplanted stem cells serving as biobridges for initiation of endogenous repair mechanisms. This is the first report of a stem cell-paved "biobridge". Indeed, to date the two major schools of discipline in stem cell repair mechanism primarily support the concept of "cell replacement" and bystander effects of "trophic factor secretion". The present novel observations of a stem cell seducing a host cell to engage in brain repair advances basic science concepts on stem cell biology and extracellular matrix, as well as provokes translational research on propagating this stem cell-paved biobridge beyond cell replacement and trophic factor secretion for the treatment of traumatic brain injury and other neurological disorders.

The Implications of the Cancer Stem Cell Hypothesis for Neuro-Oncology and Neurology.

PubMed

Rich, Jeremy N

2008-05-01

The cancer stem cell hypothesis posits that cancers contain a subset of neoplastic cells that propagate and maintain tumors through sustained self-renewal and potent tumorigenecity. Recent excitement has been generated by a number of reports that have demonstrated the existence of cancer stem cells in several types of brain tumors. Brain cancer stem cells - also called tumor initiating cells or tumor propagating cells - share features with normal neural stem cells but do not necessarily originate from stem cells. Although most cancers have only a small fraction of cancer stem cells, these tumor cells have been shown in laboratory studies to contribute to therapeutic resistance, formation of new blood vessels to supply the tumor, and tumor spread. As malignant brain tumors rank among the deadliest of all neurologic diseases, the identification of new cellular targets may have profound implications in neuro-oncology. Novel drugs that target stem cell pathways active in brain tumors have been efficacious against cancer stem cells suggesting that anti-cancer stem cell therapies may advance brain tumor therapy. The cancer stem cell hypothesis may have several implications for other neurologic diseases as caution must be exercised in activating stem cell maintenance pathways in cellular therapies for neurodegenerative diseases. The ability for a small fraction of cells to determine the overall course of a disease may also inform new paradigms of disease that may translate into improved patient outcomes.

Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status.

PubMed

Eichler, L; Bellenberg, B; Hahn, H K; Köster, O; Schöls, L; Lukas, C

2011-05-01

Cerebellar and brain stem atrophy are important features in SCA3, whereas SCA6 has been regarded as a "pure" cerebellar disease. However, recent neuropathologic studies have described additional brain stem involvement in SCA6. We, therefore, aimed to investigate the occurrence and impact of regional infratentorial brain volume differences in patients with SCA3 and SCA6. Thirty-four patients with genetically proved SCA (SCA3, n = 17; SCA6, n = 17) and age-matched healthy control subjects (n = 51) were included. In all subjects, high-resolution T1-weighted images were acquired with a 1.5T MR imaging scanner. Individual brain stem and cerebellar volumes were calculated by using semiautomated volumetry approaches. For all patients with SCA, clinical dysfunction was scored according to the ICARS. Multiple regression analysis was used to identify the contribution of regional volumes to explain the variance in clinical dysfunction in each SCA genotype. Cerebellar volumes were lower in patients with SCA6 compared with controls and with those with SCA3. In contrast to controls, brain stem volume loss was observed in patients with SCA3 (P < .001) and, to a lesser extent, in those with SCA6 (P = .027). Significant linear dependencies were found between ICARS and cerebellum volume (SCA3: R(2) = 0.29, P = .02; SCA6: R(2) = 0.29, P = .03) and between ICARS and brain stem volume (SCA3: R(2) = 0.49, P = .002; SCA6: R(2) = 0.39, P < .01) in both subtypes. Both cerebellar and brain stem atrophy contributed independently to the variance in clinical dysfunction in SCA6, while in SCA3, only brain stem atrophy was of relevance. Our current findings in accordance with recent neuroradiologic and pathoanatomic studies suggest brain stem and cerebellar volume loss as attractive surrogate markers of disease severity in SCA3 and SCA6.

Brain stem slice conditioned medium contains endogenous BDNF and GDNF that affect neural crest boundary cap cells in co-culture.

PubMed

Kaiser, Andreas; Kale, Ajay; Novozhilova, Ekaterina; Siratirakun, Piyaporn; Aquino, Jorge B; Thonabulsombat, Charoensri; Ernfors, Patrik; Olivius, Petri

2014-05-30

Conditioned medium (CM), made by collecting medium after a few days in cell culture and then re-using it to further stimulate other cells, is a known experimental concept since the 1950s. Our group has explored this technique to stimulate the performance of cells in culture in general, and to evaluate stem- and progenitor cell aptitude for auditory nerve repair enhancement in particular. As compared to other mediums, all primary endpoints in our published experimental settings have weighed in favor of conditioned culture medium, where we have shown that conditioned culture medium has a stimulatory effect on cell survival. In order to explore the reasons for this improved survival we set out to analyze the conditioned culture medium. We utilized ELISA kits to investigate whether brain stem (BS) slice CM contains any significant amounts of brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF). We further looked for a donor cell with progenitor characteristics that would be receptive to BDNF and GDNF. We chose the well-documented boundary cap (BC) progenitor cells to be tested in our in vitro co-culture setting together with cochlear nucleus (CN) of the BS. The results show that BS CM contains BDNF and GDNF and that survival of BC cells, as well as BC cell differentiation into neurons, were enhanced when BS CM were used. Altogether, we conclude that BC cells transplanted into a BDNF and GDNF rich environment could be suitable for treatment of a traumatized or degenerated auditory nerve. Copyright © 2014 Elsevier B.V. All rights reserved.

Activation of PI3K/Akt signaling in rostral ventrolateral medulla impairs brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication.

PubMed

Tsai, Ching-Yi; Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H

2014-03-01

As the most widely used pesticides in the globe, the organophosphate compounds are understandably linked with the highest incidence of suicidal poisoning. Whereas the elicited toxicity is often associated with circulatory depression, the underlying mechanisms require further delineation. Employing the pesticide mevinphos as our experimental tool, we evaluated the hypothesis that transcriptional upregulation of nitric oxide synthase II (NOS II) by NF-κB on activation of the PI3K/Akt cascade in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, underpins the circulatory depressive effects of organophosphate poisons. Microinjection of mevinphos (10 nmol) bilaterally into the RVLM of anesthetized Sprague-Dawley rats induced a progressive hypotension that was accompanied sequentially by an increase (Phase I) and a decrease (Phase II) of an experimental index for the baroreflex-mediated sympathetic vasomotor tone. There were also progressive augmentations in PI3K or Akt enzyme activity and phosphorylation of p85 or Akt(Thr308) subunit in the RVLM that were causally related to an increase in NF-κB transcription activity and elevation in NOS II or peroxynitrite expression. Loss-of-function manipulations of PI3K or Akt in the RVLM significantly antagonized the reduced baroreflex-mediated sympathetic vasomotor tone and hypotension during Phase II mevinphos intoxication, and blunted the increase in NF-κB/NOS II/peroxynitrite signaling. We conclude that activation of the PI3K/Akt cascade, leading to upregulation of NF-κB/NOS II/peroxynitrite signaling in the RVLM, elicits impairment of brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication. Copyright © 2014 Elsevier Inc. All rights reserved.

New Clinically Feasible 3T MRI Protocol to Discriminate Internal Brain Stem Anatomy.

PubMed

Hoch, M J; Chung, S; Ben-Eliezer, N; Bruno, M T; Fatterpekar, G M; Shepherd, T M

2016-06-01

Two new 3T MR imaging contrast methods, track density imaging and echo modulation curve T2 mapping, were combined with simultaneous multisection acquisition to reveal exquisite anatomic detail at 7 canonical levels of the brain stem. Compared with conventional MR imaging contrasts, many individual brain stem tracts and nuclear groups were directly visualized for the first time at 3T. This new approach is clinically practical and feasible (total scan time = 20 minutes), allowing better brain stem anatomic localization and characterization. © 2016 by American Journal of Neuroradiology.

Stem cells for brain repair in neonatal hypoxia-ischemia.

PubMed

Chicha, L; Smith, T; Guzman, R

2014-01-01

Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.

Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition

PubMed Central

Eyler, Christine E.; Foo, Wen-Chi; LaFiura, Katherine M.; McLendon, Roger E.; Hjelmeland, Anita B.; Rich, Jeremy N.

2009-01-01

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer improved efficacy and reduced toxicity compared to conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biologies may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched non-stem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anti-cancer stem cell therapies. PMID:18802038

Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice

PubMed Central

Ngwenya, Laura B.; Mazumder, Sarmistha; Porter, Zachary R.; Oswald, Duane J.

2018-01-01

Cognitive deficits after traumatic brain injury (TBI) are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI) in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC). Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation. PMID:29531536

Being a Neural Stem Cell: A Matter of Character But Defined by the Microenvironment.

PubMed

Andreopoulou, Evangelia; Arampatzis, Asterios; Patsoni, Melina; Kazanis, Ilias

2017-01-01

The cells that build the nervous system, either this is a small network of ganglia or a complicated primate brain, are called neural stem and progenitor cells. Even though the very primitive and the very recent neural stem cells (NSCs) share common basic characteristics that are hard-wired within their character, such as the expression of transcription factors of the SoxB family, their capacity to give rise to extremely different neural tissues depends significantly on instructions from the microenvironment. In this chapter we explore the nature of the NSC microenvironment, looking through evolution, embryonic development, maturity and even disease. Experimental work undertaken over the last 20 years has revealed exciting insight into the NSC microcosmos. NSCs are very capable in producing their own extracellular matrix and in regulating their behaviour in an autocrine and paracrine manner. Nevertheless, accumulating evidence indicates an important role for the vasculature, especially within the NSC niches of the postnatal brain; while novel results reveal direct links between the metabolic state of the organism and the function of NSCs.

Neural stem cell-based dual suicide gene delivery for metastatic brain tumors.

PubMed

Wang, C; Natsume, A; Lee, H J; Motomura, K; Nishimira, Y; Ohno, M; Ito, M; Kinjo, S; Momota, H; Iwami, K; Ohka, F; Wakabayashi, T; Kim, S U

2012-11-01

In our previous works, we demonstrated that human neural stem cells (NSCs) transduced with the cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on glioma and medulloblastoma cells after administration of the prodrug 5-fluorocytosine (5-FC). In addition, herpes simplex virus thymidine kinase (TK) is a widely studied enzyme used for suicide gene strategies, for which the prodrug is ganciclovir (GCV). To apply this strategy to brain metastasis treatment, we established here a human NSC line (F3.CD-TK) expressing the dual suicide genes CD and TK. We examined whether F3.CD-TK cells intensified the antitumor effect on lung cancer brain metastases. In vitro studies showed that F3.CD-TK cells exerted a marked bystander effect on human lung cancer cells after treatment with 5-FC and GCV. In a novel experimental brain metastases model, intravenously administered F3 cells migrated near lung cancer metastatic lesions, which were induced by the injection of lung cancer cells via the intracarotid artery. More importantly, F3.CD-TK cells in the presence of prodrugs 5-FC and GCV decreased tumor size and considerably prolonged animal survival. The results of the present study indicate that the dual suicide gene-engineered, NSC-based treatment strategy might offer a new promising therapeutic modality for brain metastases.

Indicators used in livestock to assess unconsciousness after stunning: a review.

PubMed

Verhoeven, M T W; Gerritzen, M A; Hellebrekers, L J; Kemp, B

2015-02-01

Assessing unconsciousness is important to safeguard animal welfare shortly after stunning at the slaughter plant. Indicators that can be visually evaluated are most often used when assessing unconsciousness, as they can be easily applied in slaughter plants. These indicators include reflexes originating from the brain stem (e.g. eye reflexes) or from the spinal cord (e.g. pedal reflex) and behavioural indicators such as loss of posture, vocalisations and rhythmic breathing. When physically stunning an animal, for example, captive bolt, most important indicators looked at are posture, righting reflex, rhythmic breathing and the corneal or palpebral reflex that should all be absent if the animal is unconscious. Spinal reflexes are difficult as a measure of unconsciousness with this type of stunning, as they may occur more vigorous. For stunning methods that do not physically destroy the brain, for example, electrical and gas stunning, most important indicators looked at are posture, righting reflex, natural blinking response, rhythmic breathing, vocalisations and focused eye movement that should all be absent if the animal is unconscious. Brain stem reflexes such as the cornea reflex are difficult as measures of unconsciousness in electrically stunned animals, as they may reflect residual brain stem activity and not necessarily consciousness. Under commercial conditions, none of the indicators mentioned above should be used as a single indicator to determine unconsciousness after stunning. Multiple indicators should be used to determine unconsciousness and sufficient time should be left for the animal to die following exsanguination before starting invasive dressing procedures such as scalding or skinning. The recording and subsequent assessment of brain activity, as presented in an electroencephalogram (EEG), is considered the most objective way to assess unconsciousness compared with reflexes and behavioural indicators, but is only applied in experimental set-ups. Studies performed in an experimental set-up have often looked at either the EEG or reflexes and behavioural indicators and there is a scarcity of studies that correlate these different readout parameters. It is recommended to study these correlations in more detail to investigate the validity of reflexes and behavioural indicators and to accurately determine the point in time at which the animal loses consciousness.

Brain-stem laceration and blunt rupture of thoracic aorta: is the intrapleural bleeding postmortem in origin?: an autopsy study.

PubMed

Zivković, Vladimir; Nikolić, Slobodan; Babić, Dragan; Juković, Fehim

2011-12-01

Some of the fatally injured car occupants could have had both blunt rupture of thoracic aorta with great amount of intrapleural blood, and pontomedullar laceration of brain-stem as well, with both injuries being fatal. The aim of this study was to answer if all intrapleural bleeding in these cases was antemortem, or the bleeding could also be partially postmortem. We observed the group of 66 cases of blunt aortic rupture: 21 case with brain-stem laceration, and 45 cases without it. The average amount of intrapleural bleeding in cases without brain-stem laceration (1993 ± 831 mL) was significantly higher than in those with this injury (1100 ± 708 mL) (t = 4.252, df = 64, P = 0.000). According to our results, in cases of the thoracic aorta rupture with concomitant brain-stem laceration, the amount of intrapleural bleeding less than 1500 mL, should be considered mostly as postmortem in origin, and in such cases, only the brain-stem injury should be considered as cause of death.

High-fat diet-induced downregulation of anorexic leukemia inhibitory factor in the brain stem.

PubMed

Licursi, Maria; Alberto, Christian O; Dias, Alex; Hirasawa, Kensuke; Hirasawa, Michiru

2016-11-01

High-fat diet (HFD) is known to induce low-grade hypothalamic inflammation. Whether inflammation occurs in other brain areas remains unknown. This study tested the effect of short-term HFD on cytokine gene expression and identified leukemia inhibitory factor (LIF) as a responsive cytokine in the brain stem. Thus, functional and cellular effects of LIF in the brain stem were investigated. Male rats were fed chow or HFD for 3 days, and then gene expression was analyzed in different brain regions for IL-1β, IL-6, TNF-α, and LIF. The effect of intracerebroventricular injection of LIF on chow intake and body weight was also tested. Patch clamp recording was performed in the nucleus tractus solitarius (NTS). HFD increased pontine TNF-α mRNA while downregulating LIF in all major parts of the brain stem, but not in the hypothalamus or hippocampus. LIF injection into the cerebral aqueduct suppressed food intake without conditioned taste aversion, suggesting that LIF can induce anorexia via lower brain regions without causing malaise. In the NTS, a key brain stem nucleus for food intake regulation, LIF induced acute changes in neuronal excitability. HFD-induced downregulation of anorexic LIF in the brain stem may provide a permissive condition for HFD overconsumption. This may be at least partially mediated by the NTS. © 2016 The Obesity Society.

Therapeutics with SPION-labeled stem cells for the main diseases related to brain aging: a systematic review.

PubMed

Alvarim, Larissa T; Nucci, Leopoldo P; Mamani, Javier B; Marti, Luciana C; Aguiar, Marina F; Silva, Helio R; Silva, Gisele S; Nucci-da-Silva, Mariana P; DelBel, Elaine A; Gamarra, Lionel F

2014-01-01

The increase in clinical trials assessing the efficacy of cell therapy for structural and functional regeneration of the nervous system in diseases related to the aging brain is well known. However, the results are inconclusive as to the best cell type to be used or the best methodology for the homing of these stem cells. This systematic review analyzed published data on SPION (superparamagnetic iron oxide nanoparticle)-labeled stem cells as a therapy for brain diseases, such as ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and dementia. This review highlights the therapeutic role of stem cells in reversing the aging process and the pathophysiology of brain aging, as well as emphasizing nanotechnology as an important tool to monitor stem cell migration in affected regions of the brain.

Comparative brain stem lesions on MRI of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis.

PubMed

Lu, Zhengqi; Zhang, Bingjun; Qiu, Wei; Kang, Zhuang; Shen, Liping; Long, Youming; Huang, Junqi; Hu, Xueqiang

2011-01-01

Brain stem lesions are common in patients with acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and multiple sclerosis (MS). To investigate comparative brain stem lesions on magnetic resonance imaging (MRI) among adult patients with ADEM, NMO, and MS. Sixty-five adult patients with ADEM (n = 17), NMO (n = 23), and MS (n = 25) who had brain stem lesions on MRI were enrolled. Morphological features of brain stem lesions among these diseases were assessed. Patients with ADEM had a higher frequency of midbrain lesions than did patients with NMO (94.1% vs. 17.4%, P<0.001) and MS (94.1% vs. 40.0%, P<0.001); patients with NMO had a lower frequency of pons lesions than did patients with MS (34.8% vs. 84.0%, P<0.001) and ADEM (34.8% vs. 70.6%, P = 0.025); and patients with NMO had a higher frequency of medulla oblongata lesions than did patients with ADEM (91.3% vs. 35.3%, P<0.001) and MS (91.3% vs. 36.0%, P<0.001). On the axial section of the brain stem, the majority (82.4%) of patients with ADEM showed lesions on the ventral part; the brain stem lesions in patients with NMO were typically located in the dorsal part (91.3%); and lesions in patients with MS were found in both the ventral (44.0%) and dorsal (56.0%) parts. The lesions in patients with ADEM (100%) and NMO (91.3%) had poorly defined margins, while lesions of patients with MS (76.0%) had well defined margins. Brain stem lesions in patients with ADEM were usually bilateral and symmetrical (82.4%), while lesions in patients with NMO (87.0%) and MS (92.0%) were asymmetrical or unilateral. Brain stem lesions showed various morphological features among adult patients with ADEM, NMO, and MS. The different lesion locations may be helpful in distinguishing these diseases.

Comparative Brain Stem Lesions on MRI of Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, and Multiple Sclerosis

PubMed Central

Kang, Zhuang; Shen, Liping; Long, Youming; Huang, Junqi; Hu, Xueqiang

2011-01-01

Background Brain stem lesions are common in patients with acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and multiple sclerosis (MS). Objectives To investigate comparative brain stem lesions on magnetic resonance imaging (MRI) among adult patients with ADEM, NMO, and MS. Methods Sixty-five adult patients with ADEM (n = 17), NMO (n = 23), and MS (n = 25) who had brain stem lesions on MRI were enrolled. Morphological features of brain stem lesions among these diseases were assessed. Results Patients with ADEM had a higher frequency of midbrain lesions than did patients with NMO (94.1% vs. 17.4%, P<0.001) and MS (94.1% vs. 40.0%, P<0.001); patients with NMO had a lower frequency of pons lesions than did patients with MS (34.8% vs. 84.0%, P<0.001) and ADEM (34.8% vs. 70.6%, P = 0.025); and patients with NMO had a higher frequency of medulla oblongata lesions than did patients with ADEM (91.3% vs. 35.3%, P<0.001) and MS (91.3% vs. 36.0%, P<0.001). On the axial section of the brain stem, the majority (82.4%) of patients with ADEM showed lesions on the ventral part; the brain stem lesions in patients with NMO were typically located in the dorsal part (91.3%); and lesions in patients with MS were found in both the ventral (44.0%) and dorsal (56.0%) parts. The lesions in patients with ADEM (100%) and NMO (91.3%) had poorly defined margins, while lesions of patients with MS (76.0%) had well defined margins. Brain stem lesions in patients with ADEM were usually bilateral and symmetrical (82.4%), while lesions in patients with NMO (87.0%) and MS (92.0%) were asymmetrical or unilateral. Conclusions Brain stem lesions showed various morphological features among adult patients with ADEM, NMO, and MS. The different lesion locations may be helpful in distinguishing these diseases. PMID:21853047

Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury☆

PubMed Central

Jiang, Jindou; Bu, Xingyao; Liu, Meng; Cheng, Peixun

2012-01-01

Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5-bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury. PMID:25806058

Brain stem sites mediating specific and non-specific temperature effects on thermoregulation in the pekin duck.

PubMed Central

Martin, R; Simon, E; Simon-Oppermann, C

1981-01-01

1. Thermodes were chronically implanted into various levels of the brain stem of sixteen Pekin ducks. The effects of local thermal stimulation on metabolic heat production, core temperature, peripheral skin temperature and respiratory frequency were investigated. 2. Four areas of thermode positions were determined according to the responses observed and were histologically identified at the end of the investigation. 3. Thermal stimulation of the lower mid-brain/upper pontine brain stem (Pos. III) elicited an increase in metabolic heat production, cutaneous vasoconstriction and rises in core temperature in response to cooling at thermoneutral and cold ambient conditions and, further, inhibition of panting by cooling and activation of panting by heating at warm ambient conditions. The metabolic response to cooling this brain stem section amounted to -0.1 W/kg. degrees C as compared with -7 W/kg. degrees C in response to total body cooling. 4. Cooling of the anterior and middle hypothalamus (Pos. II) caused vasodilatation in the skin and did not elicit shivering. The resulting drop in core temperature at a given degree of cooling was greater than the rise in core temperature in response to equivalent cooling of the lower mid-brain/upper pontine brain stem. 5. Cooling of the preoptic forebrain (Pos. I) and of the myelencephalon (Pos. IV) did not elicit thermoregulatory reactions. 6. It is concluded that the duck's brain stem contains thermoreceptive structures in the lower mid-brain/upper pontine section. However, the brain stem as a whole appears to contribute little to cold defence during general hypothermia because of the inhibitory effects originating in the anterior and middle hypothalamus. Cold defence in the duck, which is comparable in strength to that in mammals, has to rely on extracerebral thermosensory structures. PMID:7310688

Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution.

PubMed

Sauer, Roland; Gölitz, Philipp; Jacobi, Johannes; Schwab, Stefan; Linker, Ralf A; Lee, De-Hyung

2017-04-15

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells.

PubMed

Nakagomi, Takayuki; Kubo, Shuji; Nakano-Doi, Akiko; Sakuma, Rika; Lu, Shan; Narita, Aya; Kawahara, Maiko; Taguchi, Akihiko; Matsuyama, Tomohiro

2015-06-01

Brain vascular pericytes (PCs) are a key component of the blood-brain barrier (BBB)/neurovascular unit, along with neural and endothelial cells. Besides their crucial role in maintaining the BBB, increasing evidence shows that PCs have multipotential stem cell activity. However, their multipotency has not been considered in the pathological brain, such as after an ischemic stroke. Here, we examined whether brain vascular PCs following ischemia (iPCs) have multipotential stem cell activity and differentiate into neural and vascular lineage cells to reconstruct the BBB/neurovascular unit. Using PCs extracted from ischemic regions (iPCs) from mouse brains and human brain PCs cultured under oxygen/glucose deprivation, we show that PCs developed stemness presumably through reprogramming. The iPCs revealed a complex phenotype of angioblasts, in addition to their original mesenchymal properties, and multidifferentiated into cells from both a neural and vascular lineage. These data indicate that under ischemic/hypoxic conditions, PCs can acquire multipotential stem cell activity and can differentiate into major components of the BBB/neurovascular unit. Thus, these findings support the novel concept that iPCs can contribute to both neurogenesis and vasculogenesis at the site of brain injuries. © 2015 AlphaMed Press.

Roles of mTOR Signaling in Brain Development.

PubMed

Lee, Da Yong

2015-09-01

mTOR is a serine/threonine kinase composed of multiple protein components. Intracellular signaling of mTOR complexes is involved in many of physiological functions including cell survival, proliferation and differentiation through the regulation of protein synthesis in multiple cell types. During brain development, mTOR-mediated signaling pathway plays a crucial role in the process of neuronal and glial differentiation and the maintenance of the stemness of neural stem cells. The abnormalities in the activity of mTOR and its downstream signaling molecules in neural stem cells result in severe defects of brain developmental processes causing a significant number of brain disorders, such as pediatric brain tumors, autism, seizure, learning disability and mental retardation. Understanding the implication of mTOR activity in neural stem cells would be able to provide an important clue in the development of future brain developmental disorder therapies.

A case of a brain stem abscess with a favorable outcome

PubMed Central

Bulthuis, Vincent J.; Gubler, Felix S.; Teernstra, Onno P. M.; Temel, Yasin

2015-01-01

Background: A brain stem abscess is a rare and severe medical condition. Here, we present a rare case of a brain stem abscess in a young pregnant woman, requiring acute stereotactic intervention. Case Description: A 36-year-old woman presented with a headache, nausea, and vomiting, and computed tomography showed a space-occupying lesion in the brain stem. She became shortly after comatose, and we decided to perform an acute stereotactic aspiration of the abscess. Soon after surgery, her neurological condition improved dramatically. Conclusion: A brainstem abscess is a life-threatening condition with a potentially good outcome if treated adequately. PMID:26543670

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed Central

Shah, Khalid

2016-01-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. PMID:27282399

Brain stem NOS and ROS in neural mechanisms of hypertension.

PubMed

Chan, Samuel H H; Chan, Julie Y H

2014-01-01

There is now compelling evidence to substantiate the notion that by depressing baroreflex regulation of blood pressure and augmenting central sympathetic outflow through their actions on the nucleus tractus solitarii (NTS) and rostral ventrolateral medulla (RVLM), brain stem nitric oxide synthase (NOS) and reactive oxygen species (ROS) are important contributing factors to neural mechanisms of hypertension. This review summarizes our contemporary views on the impact of NOS and ROS in the NTS and RVLM on neurogenic hypertension, and presents potential antihypertensive strategies that target brain stem NOS/ROS signaling. NO signaling in the brain stem may be pro- or antihypertensive depending on the NOS isoform that generates this gaseous moiety and the site of action. Elevation of the ROS level when its production overbalances its degradation in the NTS and RVLM underlies neurogenic hypertension. Interventional strategies with emphases on alleviating the adverse actions of these molecules on blood pressure regulation have been investigated. The pathological roles of NOS in the RVLM and NTS in neural mechanisms of hypertension are highly complex. Likewise, multiple signaling pathways underlie the deleterious roles of brain-stem ROS in neurogenic hypertension. There are recent indications that interactions between brain stem ROS and NOS may play a contributory role. Given the complicity of action mechanisms of brain-stem NOS and ROS in neural mechanisms of hypertension, additional studies are needed to identify the most crucial therapeutic target that is applicable not only in animal models but also in patients suffering from neurogenic hypertension.

Diffusion-weighted imaging score of the brain stem: A predictor of outcome in acute basilar artery occlusion treated with the Solitaire FR device.

PubMed

Mourand, I; Machi, P; Nogué, E; Arquizan, C; Costalat, V; Picot, M-C; Bonafé, A; Milhaud, D

2014-06-01

The prognosis for ischemic stroke due to acute basilar artery occlusion is very poor: Early recanalization remains the main factor that can improve outcomes. The baseline extent of brain stem ischemic damage can also influence outcomes. We evaluated the validity of an easy-to-use DWI score to predict clinical outcome in patients with acute basilar artery occlusion treated by mechanical thrombectomy. We analyzed the baseline clinical and DWI parameters of 31 patients with acute basilar artery occlusion, treated within 24 hours of symptom onset by using a Solitaire FR device. The DWI score of the brain stem was assessed with a 12-point semiquantitative score that separately considered each side of the medulla, pons, and midbrain. Clinical outcome was assessed at 180 days by using the mRS. According to receiver operating characteristic analyses, the cutoff score determined the optimal positive predictive value for outcome. The Spearman rank correlation coefficient assessed the correlation between the DWI brain stem score and baseline characteristics. Successful recanalization (Thrombolysis in Cerebral Infarction 3-2b) was achieved in 23 patients (74%). A favorable outcome (mRS ≤ 2) was observed in 11 patients (35%). An optimal DWI brain stem score of <3 predicted a favorable outcome. The probability of a very poor outcome (mRS ≥ 5) if the DWI brain stem score was ≥5 reached 80% (positive predictive value) and 100% if this score was ≥6. Interobserver reliability of the DWI brain stem score was excellent, with an intraclass correlation coefficient of 0.97 (95% CI, 0.96-0.99). The DWI brain stem score was significantly associated with baseline tetraplegia (P = .001) and coma (P = .005). In patients with acute basilar artery occlusion treated by mechanical thrombectomy, the baseline DWI brain lesion score seems to predict clinical outcome. © 2014 by American Journal of Neuroradiology.

Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link?

PubMed Central

Germano, Isabelle; Swiss, Victoria; Casaccia, Patrizia

2010-01-01

The discovery of brain tumor-derived cells (BTSC) with the properties of stem cells has led to the formulation of the hypothesis that neural stem cells could be the cell of origin of primary brain tumors (PBT). In this review we present the most common molecular changes in PBT, define the criteria of identification of BTSC and discuss the similarities between the characteristics of these cells and those of the endogenous population of neural stem cells (NPCs) residing in germinal areas of the adult brain. Finally, we propose possible mechanisms of cancer initiation and progression and suggest a model of tumor initiation that includes intrinsic changes of resident NSC and potential changes in the microenvironment defining the niche where the NSC reside. PMID:20045420

Confounding Brain Stem Function During Pediatric Brain Death Determination: Two Case Reports.

PubMed

Hansen, Gregory; Joffe, Ari R

2017-06-01

A patient who has been declared brain dead is considered to be both legally and clinically dead. However, we report 2 pediatric cases in which the patients demonstrated clinical signs of brain stem function that are not recognized or tested in current Canadian or US guidelines.

Childhood Brain Stem Glioma Treatment (PDQ®)—Health Professional Version

Cancer.gov

Childhood brain stem glioma presents as a diffuse intrinsic pontine glioma (DIPG; a fast-growing tumor that is difficult to treat and has a poor prognosis) or a focal glioma (grows more slowly, is easier to treat, and has a better prognosis). Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed summary.

Controlling micro- and nano-environment of tumor and stem cells for novel research and therapy of brain cancer

NASA Astrophysics Data System (ADS)

Smith, Christopher Lloyd

The use of modern technologies in cancer research has engendered a great deal of excitement. Many of these advanced approaches involve in-depth mathematical analyses of the inner working of cells, via genomic and proteomic analyses. However these techniques may not be ideal for the study of complex cell phenotypes and behaviors. This dissertation explores cancer and potential therapies through phenotypic analysis of cell behaviors, an alternative approach. We employ this experimental framework to study brain cancer (glioma), a particularly formidable example of this diverse ailment. Through the application of micro- and nanotechnology, we carefully control the surrounding environments of cells to understand their responses to various cues and to manipulate their behaviors. Subsequently we obtain clinically relevant information that allows better understanding of glioma, and enhancement of potential therapies. We first aim to address brain tumor dispersal, through analysis of cell migration. Utilizing nanometer-scale topographic models of the extracellular matrix, we study the migratory response of glioma cells to various stimuli in vitro. Second, we implement knowledge gained from these investigations to define characteristics of tumor progression in patients, and to develop treatments inhibiting cell migration. Next we use microfluidic and nanotopographic models to study the behaviors of stem cells in vitro. Here we attempt to improve their abilities to deliver therapeutic proteins to cancer, an innovative treatment approach. We analyze the multi-step process by which adipose-derived stem cells naturally home to tumor sites, and identify numerous environmental perturbations to enhance this behavior. Finally, we attempt to demonstrate that these cell culture-based manipulations can enhance the localization of adipose stem cells to glioma in vivo using animal models. Throughout this work we utilize environmental cues to analyze and induce particular behaviors in cells. We further demonstrate that this general technique can be used to determine clinically relevant tumor characteristics, to identify potential drug targets, and to enhance potential therapies. Therefore this thesis illuminates a novel framework for experimentation into cancer, and specifically advances two treatment approaches. We anticipate that the methodologies described in this study will prove useful to various branches of medicine and biological research.

The BRAIN Initiative Provides a Unifying Context for Integrating Core STEM Competencies into a Neurobiology Course.

PubMed

Schaefer, Jennifer E

2016-01-01

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative introduced by the Obama Administration in 2013 presents a context for integrating many STEM competencies into undergraduate neuroscience coursework. The BRAIN Initiative core principles overlap with core STEM competencies identified by the AAAS Vision and Change report and other entities. This neurobiology course utilizes the BRAIN Initiative to serve as the unifying theme that facilitates a primary emphasis on student competencies such as scientific process, scientific communication, and societal relevance while teaching foundational neurobiological content such as brain anatomy, cellular neurophysiology, and activity modulation. Student feedback indicates that the BRAIN Initiative is an engaging and instructional context for this course. Course module organization, suitable BRAIN Initiative commentary literature, sample primary literature, and important assignments are presented.

Early metabolic/cellular-level resuscitation following terminal brain stem herniation: implications for organ transplantation.

PubMed

Arbour, Richard B

2013-01-01

Patients with terminal brain stem herniation experience global physiological consequences and represent a challenging population in critical care practice as a result of multiple factors. The first factor is severe depression of consciousness, with resulting compromise in airway stability and lung ventilation. Second, with increasing severity of brain trauma, progressive brain edema, mass effect, herniation syndromes, and subsequent distortion/displacement of the brain stem follow. Third, with progression of intracranial pathophysiology to terminal brain stem herniation, multisystem consequences occur, including dysfunction of the hypothalamic-pituitary axis, depletion of stress hormones, and decreased thyroid hormone bioavailability as well as biphasic cardiovascular state. Cardiovascular dysfunction in phase 1 is a hyperdynamic and hypertensive state characterized by elevated systemic vascular resistance and cardiac contractility. Cardiovascular dysfunction in phase 2 is a hypotensive state characterized by decreased systemic vascular resistance and tissue perfusion. Rapid changes along the continuum of hyperperfusion versus hypoperfusion increase risk of end-organ damage, specifically pulmonary dysfunction from hemodynamic stress and high-flow states as well as ischemic changes consequent to low-flow states. A pronounced inflammatory state occurs, affecting pulmonary function and gas exchange and contributing to hemodynamic instability as a result of additional vasodilatation. Coagulopathy also occurs as a result of consumption of clotting factors as well as dilution of clotting factors and platelets consequent to aggressive crystalloid administration. Each consequence of terminal brain stem injury complicates clinical management within this patient demographic. In general, these multisystem consequences are managed with mechanism-based interventions within the context of caring for the donor's organs (liver, kidneys, heart, etc.) after death by neurological criteria. These processes begin far earlier in the continuum of injury, at the moment of terminal brain stem herniation. As such, aggressive, mechanism-based care, including hormonal replacement therapy, becomes clinically appropriate before formal brain death declaration to support cardiopulmonary stability following terminal brain stem herniation.

New experimental models of the blood-brain barrier for CNS drug discovery

PubMed Central

Kaisar, Mohammad A.; Sajja, Ravi K.; Prasad, Shikha; Abhyankar, Vinay V.; Liles, Taylor; Cucullo, Luca

2017-01-01

Introduction The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms. PMID:27782770

Paraneoplastic brain stem encephalitis.

PubMed

Blaes, Franz

2013-04-01

Paraneoplastic brain stem encephalitis can occur as an isolated clinical syndrome or, more often, may be part of a more widespread encephalitis. Different antineuronal autoantibodies, such as anti-Hu, anti-Ri, and anti-Ma2 can be associated with the syndrome, and the most frequent tumors are lung and testicular cancer. Anti-Hu-associated brain stem encephalitis does not normally respond to immunotherapy; the syndrome may stabilize under tumor treatment. Brain stem encephalitis with anti-Ma2 often improves after immunotherapy and/or tumor therapy, whereas only a minority of anti-Ri positive patients respond to immunosuppressants or tumor treatment. The Opsoclonus-myoclonus syndrome (OMS) in children, almost exclusively associated with neuroblastoma, shows a good response to steroids, ACTH, and rituximab, some patients do respond to intravenous immunoglobulins or cyclophosphamide. In adults, OMS is mainly associated with small cell lung cancer or gynecological tumors and only a small part of the patients show improvement after immunotherapy. Earlier diagnosis and treatment seem to be one major problem to improve the prognosis of both, paraneoplastic brain stem encephalitis, and OMS.

Spontaneous complete regression of a brain stem glioma pathologically diagnosed as a high-grade glioma.

PubMed

Ishihara, Masahiro; Yamamoto, Kazumi; Miwa, Hideaki; Nishi, Masaya

2017-12-01

Spontaneous regressions of brain stem gliomas are extremely rare. Only six cases have been reported in the literature. We describe the case of a patient who was diagnosed with a pontomedullary dorsal brain stem glioma at the age of 15 years. An open biopsy showed the presence of an anaplastic glioma. Because the patient and her parents refused conventional therapies, including radiation and chemotherapy, we followed up the patient by performing magnetic resonance imaging scans on her every 3 months. At 3 months after biopsy, we observed the radiological disappearance of her tumor. One year after biopsy, the tumor retained the spontaneous complete regression observed earlier. In this case report, we present the first report of the spontaneous complete regression of a brain stem glioma that was histologically proven to be a high-grade glioma and we believe that this regression was the natural progression of this case, as may be the scenario in a few other cases of brain stem gliomas.

[Therapeutic strategies targeting brain tumor stem cells].

PubMed

Toda, Masahiro

2009-07-01

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

PubMed

Lojewski, Xenia; Srimasorn, Sumitra; Rauh, Juliane; Francke, Silvan; Wobus, Manja; Taylor, Verdon; Araúzo-Bravo, Marcos J; Hallmeyer-Elgner, Susanne; Kirsch, Matthias; Schwarz, Sigrid; Schwarz, Johannes; Storch, Alexander; Hermann, Andreas

2015-10-01

Brain perivascular cells have recently been identified as a novel mesodermal cell type in the human brain. These cells reside in the perivascular niche and were shown to have mesodermal and, to a lesser extent, tissue-specific differentiation potential. Mesenchymal stem cells (MSCs) are widely proposed for use in cell therapy in many neurological disorders; therefore, it is of importance to better understand the "intrinsic" MSC population of the human brain. We systematically characterized adult human brain-derived pericytes during in vitro expansion and differentiation and compared these cells with fetal and adult human brain-derived neural stem cells (NSCs) and adult human bone marrow-derived MSCs. We found that adult human brain pericytes, which can be isolated from the hippocampus and from subcortical white matter, are-in contrast to adult human NSCs-easily expandable in monolayer cultures and show many similarities to human bone marrow-derived MSCs both regarding both surface marker expression and after whole transcriptome profile. Human brain pericytes showed a negligible propensity for neuroectodermal differentiation under various differentiation conditions but efficiently generated mesodermal progeny. Consequently, human brain pericytes resemble bone marrow-derived MSCs and might be very interesting for possible autologous and endogenous stem cell-based treatment strategies and cell therapeutic approaches for treating neurological diseases. Perivascular mesenchymal stem cells (MSCs) recently gained significant interest because of their appearance in many tissues including the human brain. MSCs were often reported as being beneficial after transplantation in the central nervous system in different neurological diseases; therefore, adult brain perivascular cells derived from human neural tissue were systematically characterized concerning neural stem cell and MSC marker expression, transcriptomics, and mesodermal and inherent neuroectodermal differentiation potential in vitro and in vivo after in utero transplantation. This study showed the lack of an innate neuronal but high mesodermal differentiation potential. Because of their relationship to mesenchymal stem cells, these adult brain perivascular mesodermal cells are of great interest for possible autologous therapeutic use. ©AlphaMed Press.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals.

PubMed

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood-brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p -aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood-brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p -aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

PubMed Central

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood–brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p-aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood–brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p-aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells. PMID:28260885

Activation of neurons in cardiovascular areas of cat brain stem affects spinal reflexes.

PubMed

Wu, W C; Wang, S D; Liu, J C; Horng, H T; Wayner, M J; Ma, J C; Chai, C Y

1994-01-01

In 65 cats anesthetized with chloralose (40 mg/kg) and urethane (400 mg/kg), the effects of electrical stimulation and microinjection of sodium glutamate (0.25 M, 100-200 nl) in the pressor areas in the rostral brain stem on the evoked L5 ventral root response (EVRR) due to intermittent stimulation of sciatic afferents were compared to stimulating the dorsomedial (DM) and ventrolateral (VLM) medulla. In general, stimulating these rostral brain stem pressor areas including the diencephalon (DIC) and rostral pons (RP) produced increases in systemic arterial pressure (SAP). In most of the cases (85%) there were associated changes in the EVRR, predominantly a decrease in EVRR (72%). Stimulation of the midbrain (MB, principally in the periaqueductal grey) produced decreases in SAP and EVRR. Decreases in EVRR was observed in 91% of the DM and VLM stimulations in which an increase in SAP was produced. This EVRR inhibition was essentially unaltered after acute midcollicular decerebration. Increases in EVRR were also observed and occurred more often in the rostral brain stem than in the medulla. Since changes of both EVRR and SAP could be reproduced by microinjection of Glu into the cardiovascular-reactive areas of the brain stem, this suggests that neuronal perikarya in these areas are responsible for both actions. On some occasions, Glu induced changes in EVRR but not in SAP. This effect occurred more frequently in the rostral brain stem than in the medulla. The present data suggest that separate neuron population exist in the brain stem for the integration of SAP and spinal reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Upregulation of FLJ10540, a PI3K-association protein, in rostral ventrolateral medulla impairs brain stem cardiovascular regulation during mevinphos intoxication.

PubMed

Tsai, Ching-Yi; Chen, Chang-Han; Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H

2015-01-01

FLJ10540, originally identified as a microtubule-associated protein, induces cell proliferation and migration during tumorigenesis via the formation of FLJ10540-PI3K complex and enhancement of PI3K kinase activity. Interestingly, activation of PI3K/Akt cascade, leading to upregulation of nitric oxide synthase II (NOS II)/peroxynitrite signaling in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, mediates the impairment of brain stem cardiovascular regulation induced by the pesticide mevinphos. We evaluated the hypothesis that upregulation of FLJ10540 in the RVLM is upstream to this repertoire of signaling cascade that underpins mevinphos-induced circulatory depression. Microinjection bilaterally of mevinphos (10nmol) into the RVLM of anesthetized Sprague-Dawley rats induced a progressive hypotension that was accompanied by an increase (Phase I), followed by a decrease (Phase II) of an experimental index for baroreflex-mediated sympathetic vasomotor tone. There was augmentation in FLJ10540 mRNA in the RVLM or FLJ10540 protein in RVLM neurons, both of which were causally and temporally related to an augmentation of binding between the catalytic subunit (p110) and regulatory subunit (p85) of PI3K, phosphorylation of Akt at Thr308 site, and NOS II, superoxide or peroxynitrite level in the RVLM. Immunoneutralization of FJL10540 in the RVLM significantly antagonized those biochemical changes, and blunted the progressive hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during mevinphos intoxication. We conclude that upregulation of FLJ10540 in the RVLM elicits impairment of brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication via activation of PI3K/Akt/NOS II/peroxynitrite signaling cascade in the RVLM. Copyright © 2014 Elsevier Inc. All rights reserved.

Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-kappaB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death.

PubMed

Chan, Julie Y H; Wu, Carol H Y; Tsai, Ching-Yi; Cheng, Hsiao-Lei; Dai, Kuang-Yu; Chan, Samuel H H; Chang, Alice Y W

2007-06-15

As the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this vital phenomenon. Using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult, we evaluated the hypothesis that transcriptional up-regulation of nitric oxide synthase I or II (NOS I or II) gene expression by nuclear factor-kappaB (NF-kappaB) on activation of muscarinic receptors in the RVLM underlies brain stem death. In Sprague-Dawley rats maintained under propofol anaesthesia, co-microinjection of muscarinic M2R (methoctramine) or M4R (tropicamide), but not M1R (pirenzepine) or M3R (4-diphenylacetoxy-N-dimethylpiperidinium) antagonist significantly reduced the enhanced NOS I-protein kinase G signalling ('pro-life' phase) or augmented NOS II-peroxynitrite cascade ('pro-death' phase) in ventrolateral medulla, blunted the biphasic increase and decrease in baroreceptor reflex-mediated sympathetic vasomotor tone that reflect the transition from life to death, and diminished the elevated DNA binding activity or nucleus-bound translocation of NF-kappaB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-kappaB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded kappaB decoy DNA preferentially antagonized the augmented NOS II-peroxynitrite cascade and the associated cardiovascular depression exhibited during the 'pro-death' phase. We conclude that transcriptional up-regulation of NOS II gene expression by activation of NF-kappaB on selective stimulation of muscarinic M2 or M4 subtype receptors in the RVLM underlies the elicited cardiovascular depression during the 'pro-death' phase in our Mev intoxication model of brain stem death.

Brain stem hypoplasia associated with Cri-du-Chat syndrome.

PubMed

Hong, Jin Ho; Lee, Ha Young; Lim, Myung Kwan; Kim, Mi Young; Kang, Young Hye; Lee, Kyung Hee; Cho, Soon Gu

2013-01-01

Cri-du-Chat syndrome, also called the 5p-syndrome, is a rare genetic abnormality, and only few cases have been reported on its brain MRI findings. We describe the magnetic resonance imaging findings of a 1-year-old girl with Cri-du-Chat syndrome who showed brain stem hypoplasia, particularly in the pons, with normal cerebellum and diffuse hypoplasia of the cerebral hemispheres. We suggest that Cri-du-Chat syndrome chould be suspected in children with brain stem hypoplasia, particularly for those with high-pitched cries.

Regulation of body temperature in the blue-tongued lizard.

PubMed

Hammel, H T; Caldwell, F T; Abrams, R M

1967-06-02

Lizards (Tiliqua scincoides) regulated their internal body temperature by moving back and forth between 15 degrees and 45 degrees C environments to maintain colonic and brain temperatures between 30 degrees and 37 degrees C. A pair of thermodes were implanted across the preoptic region of the brain stem, and a reentrant tube for a thermocouple was implanted in the brain stem. Heating the brain stem to 41 degrees C activated the exit response from the hot environment at a colonic temperature 1 degrees to 2 degrees C lower than normal, whereas cooling the brain stem to 25 degrees C delayed the exit from the hot environment until the colonic temperature was 1 degrees to 2 degrees C higher than normal. The behavioral thermoregulatory responses of this ectotherm appear to be activated by a combination of hypothalamic and other body temperatures.

Brain mesenchymal stem cells: The other stem cells of the brain?

PubMed

Appaix, Florence; Nissou, Marie-France; van der Sanden, Boudewijn; Dreyfus, Matthieu; Berger, François; Issartel, Jean-Paul; Wion, Didier

2014-04-26

Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.

Brain mesenchymal stem cells: The other stem cells of the brain?

PubMed Central

Appaix, Florence; Nissou, Marie-France; van der Sanden, Boudewijn; Dreyfus, Matthieu; Berger, François; Issartel, Jean-Paul; Wion, Didier

2014-01-01

Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression. PMID:24772240

Evolution of brain region volumes during artificial selection for relative brain size.

PubMed

Kotrschal, Alexander; Zeng, Hong-Li; van der Bijl, Wouter; Öhman-Mägi, Caroline; Kotrschal, Kurt; Pelckmans, Kristiaan; Kolm, Niclas

2017-12-01

The vertebrate brain shows an extremely conserved layout across taxa. Still, the relative sizes of separate brain regions vary markedly between species. One interesting pattern is that larger brains seem associated with increased relative sizes only of certain brain regions, for instance telencephalon and cerebellum. Till now, the evolutionary association between separate brain regions and overall brain size is based on comparative evidence and remains experimentally untested. Here, we test the evolutionary response of brain regions to directional selection on brain size in guppies (Poecilia reticulata) selected for large and small relative brain size. In these animals, artificial selection led to a fast response in relative brain size, while body size remained unchanged. We use microcomputer tomography to investigate how the volumes of 11 main brain regions respond to selection for larger versus smaller brains. We found no differences in relative brain region volumes between large- and small-brained animals and only minor sex-specific variation. Also, selection did not change allometric scaling between brain and brain region sizes. Our results suggest that brain regions respond similarly to strong directional selection on relative brain size, which indicates that brain anatomy variation in contemporary species most likely stem from direct selection on key regions. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Nanoparticle-mediated transcriptional modification enhances neuronal differentiation of human neural stem cells following transplantation in rat brain.

PubMed

Li, Xiaowei; Tzeng, Stephany Y; Liu, Xiaoyan; Tammia, Markus; Cheng, Yu-Hao; Rolfe, Andrew; Sun, Dong; Zhang, Ning; Green, Jordan J; Wen, Xuejun; Mao, Hai-Quan

2016-04-01

Strategies to enhance survival and direct the differentiation of stem cells in vivo following transplantation in tissue repair site are critical to realizing the potential of stem cell-based therapies. Here we demonstrated an effective approach to promote neuronal differentiation and maturation of human fetal tissue-derived neural stem cells (hNSCs) in a brain lesion site of a rat traumatic brain injury model using biodegradable nanoparticle-mediated transfection method to deliver key transcriptional factor neurogenin-2 to hNSCs when transplanted with a tailored hyaluronic acid (HA) hydrogel, generating larger number of more mature neurons engrafted to the host brain tissue than non-transfected cells. The nanoparticle-mediated transcription activation method together with an HA hydrogel delivery matrix provides a translatable approach for stem cell-based regenerative therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mannitol-Enhanced Delivery of Stem Cells and Their Growth Factors Across the Blood–Brain Barrier

PubMed Central

Gonzales-Portillo, Gabriel S.; Sanberg, Paul R.; Franzblau, Max; Gonzales-Portillo, Chiara; Diamandis, Theo; Staples, Meaghan; Sanberg, Cyndy D.; Borlongan, Cesar V.

2014-01-01

Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood–brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy. PMID:24480552

Characteristics of taurine release in slices from adult and developing mouse brain stem.

PubMed

Saransaari, P; Oja, S S

2006-07-01

Taurine has been thought to function as a regulator of neuronal activity, neuromodulator and osmoregulator. Moreover, it is essential for the development and survival of neural cells and protects them under cell-damaging conditions. Taurine is also involved in many vital functions regulated by the brain stem, including cardiovascular control and arterial blood pressure. The release of taurine has been studied both in vivo and in vitro in higher brain areas, whereas the mechanisms of release have not been systematically characterized in the brain stem. The properties of release of preloaded [(3)H]taurine were now characterized in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. In general, taurine release was found to be similar to that in other brain areas, consisting of both Ca(2+)-dependent and Ca(2+)-independent components. Moreover, the release was mediated by Na(+)-, Cl(-)-dependent transporters operating outwards, as both Na(+)-free and Cl(-) -free conditions greatly enhanced it. Cl(-) channel antagonists and a Cl(-) transport inhibitor reduced the release at both ages, indicating that a part of the release occurs through ion channels. Protein kinases appeared not to be involved in taurine release in the brain stem, since substances affecting the activity of protein kinase C or tyrosine kinase had no significant effects. The release was modulated by cAMP second messenger systems and phospholipases at both ages. Furthermore, the metabotropic glutamate receptor agonists likewise suppressed the K(+)-stimulated release at both ages. In the immature brain stem, the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) potentiated taurine release in a receptor-mediated manner. This could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.

[Stem Cells in the Brain of Mammals and Human: Fundamental and Applied Aspects].

PubMed

Aleksandrova, M A; Marey, M V

2015-01-01

Brain stem cells represent an extremely intriguing phenomenon. The aim of our review is to present an integrity vision of their role in the brain of mammals and humans, and their clinical perspectives. Over last two decades, investigations of biology of the neural stem cells produced significant changes in general knowledge about the processes of development and functioning of the brain. Researches on the cellular and molecular mechanisms of NSC differentiation and behavior led to new understanding of their involvement in learning and memory. In the regenerative medicine, original therapeutic approaches to neurodegenerative brain diseases have been elaborated due to fundamental achievements in this field. They are based on specific regenerative potential of neural stem cells and progenitor cells, which possess the ability to replace dead cells and express crucially significant biologically active factors that are missing in the pathological brain. For the needs of cell substitution therapy in the neural diseases, adequate methods of maintaining stem cells in culture and their differentiation into different types of neurons and glial cells, have been developed currently. The success of modern cellular technologies has significantly expanded the range of cells used for cell therapy. The near future may bring new perspective and distinct progress in brain cell therapy due to optimizing the cells types most promising for medical needs.

Isolation of virus from brain after immunosuppression of mice with latent herpes simplex

NASA Astrophysics Data System (ADS)

Kastrukoff, Lorne; Long, Carol; Doherty, Peter C.; Wroblewska, Zofia; Koprowski, Hilary

1981-06-01

Herpes simplex virus (HSV) is usually present in a latent form in the trigeminal ganglion of man1-3. Various stress factors may induce virus reactivation, which is manifest by a lip lesion (innervated from the trigeminal ganglion) and the production of infectious virus. The considerable experimental efforts to define the conditions that lead to the reactivation of latent HSV have concentrated on isolating virus either from the original extraneural site of virus inoculation, or from cell-free homogenates of sensory ganglia from latently infected animals4-15. Recent DNA hybridization experiments resulted in the demonstration of the presence of HSV genomes in the brain tissue of both latently infected mice, and of humans who showed no clinical symptoms of HSV (ref. 16 and N. Fraser, personal communication). This led us to consider the possibility that HSV may be present in brain tissue as the result of either reactivation of the virus in brain cells or the passage of reactivated virus from trigeminal ganglia through the brain stem to the brain. The presence of infectious HSV in brain tissue has not previously been demonstrated; yet this could be a factor in chronic, relapsing neurological diseases such as multiple sclerosis. We have now shown experimentally that mice carrying latent HSV in their trigeminal ganglia may, following massive immunosuppression, express infectious virus in the central nervous system (CNS).

Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain.

PubMed

Li, Wenwu; Sun, Guoqiang; Yang, Su; Qu, Qiuhao; Nakashima, Kinichi; Shi, Yanhong

2008-01-01

TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.

Nuclear Receptor TLX Regulates Cell Cycle Progression in Neural Stem Cells of the Developing Brain

PubMed Central

Li, Wenwu; Sun, Guoqiang; Yang, Su; Qu, Qiuhao; Nakashima, Kinichi; Shi, Yanhong

2008-01-01

TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain. PMID:17901127

Pathophysiological changes of the cerebellum and brain stem in a rabbit model after superior petrosal vein sacrifice.

PubMed

Cheng, Lei; Guo, Pin; Liao, Yi-Wei; Zhang, Hong-Liang; Li, Huan-Ting; Yuan, Xianrui

2017-11-13

In certain surgical procedures sacrifice of the superior petrosal vein (SPV) is required. Previous studies have reported transient cerebellar edema, venous infarction or hemorrhage might occur after sectioning of the SPV. This study investigated the pathophysiological changes of cerebellum and brain stem after SPV sacrifice. Rabbits were divided into the operation group where the SPV was sacrificed and the control group where the SPV remained intact. Each group was further subdivided into 4, 8, 12, 24, 48 and 72 hours groups which represented the time period from sacrifice of the SPV to sacrifice of the rabbits. The water content (WC), Na + content, K + content and pathophysiological changes of cerebellum and brain stem tissue were measured. In comparison to the control, the WC and Na + content of cerebellar tissue were increased in the 4h, 8h, 12h and 24h operation subgroups (p<0.05), but only increased in the 4h subgroup of the brain stem tissue (p<0.05). The K + content of the cerebellar tissue decreased in the 4h, 8h, 12h and 24h operation subgroups (p<0.05) but only decreased in the 4h subgroup of brain stem tissue (p<0.05). Nissl staining and transmission electron microscopy demonstrated that cerebellar edema occurred in the 4h, 8h, 12h and 24h operation subgroups but not in the 48h and 72h subgroups. Brain stem edema occurred in the 4h operation subgroup. In summary, cerebellum and brain stem edema can be observed at different time points after sacrifice of the SPV in the rabbit model. ©2017 The Author(s).

Possible role of brain stem respiratory neurons in mediating vomiting during space motion sickness

NASA Technical Reports Server (NTRS)

Miller, A. D.; Tan, L. K.

1987-01-01

The object of this study was to determine if brain stem expiratory neurons control abdominal muscle activity during vomiting. The activity of 27 ventral respiratory group expiratory neurons, which are known to be of primary importance for control of abdominal muscle activity during respiration, was recorded. It is concluded that abdominal muscle activity during vomiting must be controlled not only by some brain stem expiratory neurons but also by other input(s).

Regenerative toxicology: the role of stem cells in the development of chronic toxicities.

PubMed

Canovas-Jorda, David; Louisse, Jochem; Pistollato, Francesca; Zagoura, Dimitra; Bremer, Susanne

2014-01-01

Human stem cell lines and their derivatives, as alternatives to the use of animal cells or cancer cell lines, have been widely discussed as cellular models in predictive toxicology. However, the role of stem cells in the development of long-term toxicities and carcinogenesis has not received great attention so far, despite growing evidence indicating the relationship of stem cell damage to adverse effects later in life. However, testing this in vitro is a scientific/technical challenge in particular due to the complex interplay of factors existing under physiological conditions. Current major research programs in stem cell toxicity are not aiming to demonstrate that stem cells can be targeted by toxicants. Therefore, this knowledge gap needs to be addressed in additional research activities developing technical solutions and defining appropriate experimental designs. The current review describes selected examples of the role of stem cells in the development of long-term toxicities in the brain, heart or liver and in the development of cancer. The presented examples illustrate the need to analyze the contribution of stem cells to chronic toxicity in order to make a final conclusion whether stem cell toxicities are an underestimated risk in mechanism-based safety assessments. This requires the development of predictive in vitro models allowing the assessment of adverse effects to stem cells on chronic toxicity and carcinogenicity.

Hoyeraal-Hreidarsson syndrome: magnetic resonance imaging findings.

PubMed

Kuwashima, Shigeko

2009-10-01

Hoyeraal-Hreidarsson syndrome (HH) has been defined as a severe variant of dyskeratosis congenita (DKC). We report here a case of a 6-year-old girl with HH who presented with bone marrow hypoplasia, skin pigmentation, nail dystrophy, growth retardation, and bilateral retinal hemorrhage. Brain MRI revealed cerebellar hypoplasia, hypoplasia of the corpus callosum, a small pituitary gland, a small brain stem, and focal long T2 lesions in the thalamus and brain stem. A brain computed tomography scan revealed intracranial calcification as well. To the best of our knowledge, a small pituitary gland and focal long T2 lesions in the thalamus and brain stem have never been reported as a feature of HH.

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

PubMed

Lang, Patrick Y; Gershon, Timothy R

2018-05-01

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. © 2018 WILEY Periodicals, Inc.

An efficient and scalable pipeline for epitope tagging in mammalian stem cells using Cas9 ribonucleoprotein

PubMed Central

Dewari, Pooran Singh; Southgate, Benjamin; Mccarten, Katrina; Monogarov, German; O'Duibhir, Eoghan; Quinn, Niall; Tyrer, Ashley; Leitner, Marie-Christin; Plumb, Colin; Kalantzaki, Maria; Blin, Carla; Finch, Rebecca; Bressan, Raul Bardini; Morrison, Gillian; Jacobi, Ashley M; Behlke, Mark A; von Kriegsheim, Alex; Tomlinson, Simon; Krijgsveld, Jeroen

2018-01-01

CRISPR/Cas9 can be used for precise genetic knock-in of epitope tags into endogenous genes, simplifying experimental analysis of protein function. However, Cas9-assisted epitope tagging in primary mammalian cell cultures is often inefficient and reliant on plasmid-based selection strategies. Here, we demonstrate improved knock-in efficiencies of diverse tags (V5, 3XFLAG, Myc, HA) using co-delivery of Cas9 protein pre-complexed with two-part synthetic modified RNAs (annealed crRNA:tracrRNA) and single-stranded oligodeoxynucleotide (ssODN) repair templates. Knock-in efficiencies of ~5–30%, were achieved without selection in embryonic stem (ES) cells, neural stem (NS) cells, and brain-tumor-derived stem cells. Biallelic-tagged clonal lines were readily derived and used to define Olig2 chromatin-bound interacting partners. Using our novel web-based design tool, we established a 96-well format pipeline that enabled V5-tagging of 60 different transcription factors. This efficient, selection-free and scalable epitope tagging pipeline enables systematic surveys of protein expression levels, subcellular localization, and interactors across diverse mammalian stem cells. PMID:29638216

Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication.

PubMed

Li, Faith C H; Yen, J C; Chan, Samuel H H; Chang, Alice Y W

2012-02-07

Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism. The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time. Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism. We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.

Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication

PubMed Central

2012-01-01

Background Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism. Methods The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time. Results Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism. Conclusions We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse. PMID:22313577

Topical Therapy with Mesenchymal Stem Cells Following an Acute Experimental Head Injury Has Benefits in Motor-Behavioral Tests for Rodents.

PubMed

Lam, P K; Wang, Kevin K W; Ip, Anthony W I; Ching, Don W C; Tong, Cindy S W; Lau, Henry C H; Kong, Themis H C S; Lai, Paul B S; Wong, George K C; Poon, W S

2016-01-01

The neuroprotective effects of mesenchymal stem cells (MSCs) have been reported in rodent and in preliminary clinical studies. MSCs are usually transplanted to patients by systemic infusion. However, only a few of the infused MSCs are delivered to the brain because of pulmonary trapping and the blood-brain barrier. In this study, MSCs were topically applied to the site of traumatic brain injury (TBI) and the neuroprotective effects were assessed. TBI was induced in Sprague-Dawley (SD) rats with an electromagnetically controlled cortical impact device after craniotomy was performed between the bregma and lambda, 1 mm lateral to the midline. We applied 1.5 million MSCs, derived from the adipose tissue of transgenic green fluorescent protein (GFP)-SD rats, to the exposed cerebral cortex at the injured site. The MSCs were held in position by a thin layer of fibrin. Neurological function in the test (n = 10) and control (n = 10) animals was evaluated using the rotarod test, the water maze test, and gait analysis at different time points. Within 5 days following topical application, GFP-positive cells were found in the brain parenchyma. These cells co-expressed with markers of Glial fibrillary acidic protein (GFAP), nestin, and NeuN. There was less neuronal death in CA1 and CA3 of the hippocampus in the test animals. Neurological functional recovery was significantly improved. Topically applied MSCs can migrate to the injured brain parenchyma and offer neuroprotective effects.

Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells

PubMed Central

Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi

2015-01-01

Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. PMID:25910782

The Effect of Flax Seed (Linum Usitatissimum) Hydroalcoholic Extract on Brain, Weight and Plasma Sexual Hormone Levels in Aged and Young Mice.

PubMed

Bahmanpour, Soghra; Kamali, Mahsa

2016-05-01

Flax is a food and fiber crop that is grown in some regions of the world. Its value will account for its great popularity as a food, medical and cosmetic applications. Flax fibers are taken from the stem of the plant and are two to three times as strong as cotton. In this study, we compared brain weight and plasma sex hormone levels in young and aged mice after the administration of Linum usitatissimum (flax seed) hydro alcoholic extract. In this study, 32 aged and 32 young mice were divided into 4 groups. Controls remained untreated and experimental groups were fed with flax seed hydroalcoholic extract by oral gavages during 3 weeks. After 3 weeks, the brain was removed and blood samples were collected to measure sex hormone levels by ELISA. Data analysis was done by statistical ANOVA test using SPSS version 18 (P<0.05). The results of this study shows that the brain weight of mice did not change significantly, but the sex hormone levels in the experimental groups in comparison with the control groups increased significantly (P<0.05). The hydroalcoholic extract of flax seed had no effect on the brain weight, but this extract improved the sexual hormone levels.

Severe traumatic head injury: prognostic value of brain stem injuries detected at MRI.

PubMed

Hilario, A; Ramos, A; Millan, J M; Salvador, E; Gomez, P A; Cicuendez, M; Diez-Lobato, R; Lagares, A

2012-11-01

Traumatic brain injuries represent an important cause of death for young people. The main objectives of this work are to correlate brain stem injuries detected at MR imaging with outcome at 6 months in patients with severe TBI, and to determine which MR imaging findings could be related to a worse prognosis. One hundred and eight patients with severe TBI were studied by MR imaging in the first 30 days after trauma. Brain stem injury was categorized as anterior or posterior, hemorrhagic or nonhemorrhagic, and unilateral or bilateral. Outcome measures were GOSE and Barthel Index 6 months postinjury. The relationship between MR imaging findings of brain stem injuries, outcome, and disability was explored by univariate analysis. Prognostic capability of MR imaging findings was also explored by calculation of sensitivity, specificity, and area under the ROC curve for poor and good outcome. Brain stem lesions were detected in 51 patients, of whom 66% showed a poor outcome, as expressed by the GOSE scale. Bilateral involvement was strongly associated with poor outcome (P < .05). Posterior location showed the best discriminatory capability in terms of outcome (OR 6.8, P < .05) and disability (OR 4.8, P < .01). The addition of nonhemorrhagic and anterior lesions or unilateral injuries showed the highest odds and best discriminatory capacity for good outcome. The prognosis worsens in direct relationship to the extent of traumatic injury. Posterior and bilateral brain stem injuries detected at MR imaging are poor prognostic signs. Nonhemorrhagic injuries showed the highest positive predictive value for good outcome.

Where and When to Cut? Fluorescein Guidance for Brain Stem and Spinal Cord Tumor Surgery-Technical Note.

PubMed

Molina, Eric Suero; Stummer, Walter

2017-12-29

Spinal cord and brain stem lesions require a judicious approach with an optimized trajectory due to a clustering of functions on their surfaces. Intraoperative mapping helps locate function. To confidently locate such lesions, neuronavigation alone lacks the desired accuracy and is of limited use in the spinal cord. To evaluate the clinical value of fluoresceins for initial delineation of such critically located lesions. We evaluated fluorescein guidance in the surgical resection of lesions with blood-brain barrier disruption demonstrating contrast enhancement in magnet resonance imaging in the spinal cord and in the brain stem in 3 different patients. Two patients harbored a diffuse cervical and thoracic spinal cord lesion, respectively. Another patient suffered metastatic lesions in the brain stem and at the floor of the fourth ventricle. Low-dose fluorescein (4 mg/kg body weight) was applied after anesthesia induction and visualized using the Zeiss Pentero 900 Yellow560 filter (Carl Zeiss, Oberkochen, Germany). Fluorescein was helpful for locating lesions and for defining the best possible trajectory. During resection, however, we found unspecific propagation of fluorescein within the brain stem up to 6 mm within 3 h after application. As these lesions were otherwise distinguishable from surrounding tissue, monitoring resection was not an issue. Fluorescein guidance is a feasible tool for defining surgical entry zones when aiming for surgical removal of spinal cord and brain stem lesions. Unselective fluorescein extravasation cautions against using such methodology for monitoring completeness of resection. Providing the right timing, a window of pseudoselectivity could increase fluoresceins' clinical value in these cases. © Congress of Neurological Surgeons 2017.

Engraftment of Human Mesenchymal Stem Cells in a Rat Photothrombotic Cerebral Infarction Model : Comparison of Intra-Arterial and Intravenous Infusion Using MRI and Histological Analysis

PubMed Central

Byun, Jun Soo; Kim, Jae Kyun; Jung, Jisung; Ha, Bon Chul; Park, Serah

2013-01-01

Objective This study aimed to evaluate the hypotheses that administration routes [intra-arterial (IA) vs. intravenous (IV)] affect the early stage migration of transplanted human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in acute brain infarction. Methods Male Sprague-Dawley rats (n=40) were subjected to photothrombotic infarction. Three days after photothrombotic infarction, rats were randomly allocated to one of four experimental groups [IA group : n=12, IV group : n=12, superparamagnetic iron oxide (SPIO) group : n=8, control group : n=8]. All groups were subdivided into 1, 6, 24, and 48 hours groups according to time point of sacrifice. Magnetic resonance imaging (MRI) consisting of T2 weighted image (T2WI), T2* weighted image (T2*WI), susceptibility weighted image (SWI), and diffusion weighted image of rat brain were obtained prior to and at 1, 6, 24, and 48 hours post-implantation. After final MRI, rats were sacrificed and grafted cells were analyzed in brain and lung specimen using Prussian blue and immunohistochemical staining. Results Grafted cells appeared as dark signal intensity regions at the peri-lesional zone. In IA group, dark signals in peri-lesional zone were more prominent compared with IV group. SWI showed largest dark signal followed by T2*WI and T2WI in both IA and IV groups. On Prussian blue staining, IA administration showed substantially increased migration and a large number of transplanted hBM-MSCs in the target brain than IV administration. The Prussian blue-positive cells were not detected in SPIO and control groups. Conclusion In a rat photothrombotic model of ischemic stroke, selective IA administration of human mesenchymal stem cells is more effective than IV administration. MRI and histological analyses revealed the time course of cell migration, and the numbers and distribution of hBM-MSCs delivered into the brain. PMID:24527188

Blood-brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow.

PubMed

Guerra, M; Blázquez, J L; Rodríguez, E M

2017-07-13

Despite decades of research, no compelling non-surgical therapies have been developed for foetal hydrocephalus. So far, most efforts have pointed to repairing disturbances in the cerebrospinal fluid (CSF) flow and to avoid further brain damage. There are no reports trying to prevent or diminish abnormalities in brain development which are inseparably associated with hydrocephalus. A key problem in the treatment of hydrocephalus is the blood-brain barrier that restricts the access to the brain for therapeutic compounds or systemically grafted cells. Recent investigations have started to open an avenue for the development of a cell therapy for foetal-onset hydrocephalus. Potential cells to be used for brain grafting include: (1) pluripotential neural stem cells; (2) mesenchymal stem cells; (3) genetically-engineered stem cells; (4) choroid plexus cells and (5) subcommissural organ cells. Expected outcomes are a proper microenvironment for the embryonic neurogenic niche and, consequent normal brain development.

Stem Cell Therapy: Repurposing Cell-Based Regenerative Medicine Beyond Cell Replacement.

PubMed

Napoli, Eleonora; Lippert, Trenton; Borlongan, Cesar V

2018-02-27

Stem cells exhibit simple and naive cellular features, yet their exact purpose for regenerative medicine continues to elude even the most elegantly designed research paradigms from developmental biology to clinical therapeutics. Based on their capacity to divide indefinitely and their dynamic differentiation into any type of tissue, the advent of transplantable stem cells has offered a potential treatment for aging-related and injury-mediated diseases. Recent laboratory evidence has demonstrated that transplanted human neural stem cells facilitate endogenous reparative mechanisms by initiating multiple regenerative processes in the brain neurogenic areas. Within these highly proliferative niches reside a myriad of potent regenerative molecules, including anti-inflammatory cytokines, proteomes, and neurotrophic factors, altogether representing a biochemical cocktail vital for restoring brain function in the aging and diseased brain. Here, we advance the concept of therapeutically repurposing stem cells not towards cell replacement per se, but rather exploiting the cells' intrinsic properties to serve as the host brain regenerative catalysts.

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed

Shah, Khalid

2016-08-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case without elevated white matter lactate.

PubMed

Sharma, Suvasini; Sankhyan, Naveen; Kumar, Atin; Scheper, Gert C; van der Knaap, Marjo S; Gulati, Sheffali

2011-06-01

A 17-year-old Indian boy with gradually progressive ataxia with onset at 12 years of age is described. Magnetic resonance imaging (MRI) of the brain revealed extensive, inhomogeneous signal abnormalities in the cerebral white matter, with involvement of selected tracts in the brain stem and spinal cord. The imaging findings were characteristic of leukoencephalopathy with brain stem and spinal cord involvement and high lactate, a recently described leukodystrophy. Interestingly, magnetic resonance spectroscopy of the abnormal white matter did not reveal elevated lactate. The patient was compound heterozygous for 2 new mutations in DARS2, genetically confirming the diagnosis.

A review of novel optical imaging strategies of the stroke pathology and stem cell therapy in stroke

PubMed Central

Aswendt, Markus; Adamczak, Joanna; Tennstaedt, Annette

2014-01-01

Transplanted stem cells can induce and enhance functional recovery in experimental stroke. Invasive analysis has been extensively used to provide detailed cellular and molecular characterization of the stroke pathology and engrafted stem cells. But post mortem analysis is not appropriate to reveal the time scale of the dynamic interplay between the cell graft, the ischemic lesion and the endogenous repair mechanisms. This review describes non-invasive imaging techniques which have been developed to provide complementary in vivo information. Recent advances were made in analyzing simultaneously different aspects of the cell graft (e.g., number of cells, viability state, and cell fate), the ischemic lesion (e.g., blood–brain-barrier consistency, hypoxic, and necrotic areas) and the neuronal and vascular network. We focus on optical methods, which permit simple animal preparation, repetitive experimental conditions, relatively medium-cost instrumentation and are performed under mild anesthesia, thus nearly under physiological conditions. A selection of recent examples of optical intrinsic imaging, fluorescence imaging and bioluminescence imaging to characterize the stroke pathology and engrafted stem cells are discussed. Special attention is paid to novel optimal reporter genes/probes for genetic labeling and tracking of stem cells and appropriate transgenic animal models. Requirements, advantages and limitations of these imaging platforms are critically discussed and placed into the context of other non-invasive techniques, e.g., magnetic resonance imaging and positron emission tomography, which can be joined with optical imaging in multimodal approaches. PMID:25177269

Breath-holding spells may be associated with maturational delay in myelination of brain stem.

PubMed

Vurucu, Sebahattin; Karaoglu, Abdulbaki; Paksu, Sukru M; Oz, Oguzhan; Yaman, Halil; Gulgun, Mustafa; Babacan, Oguzhan; Unay, Bulent; Akin, Ridvan

2014-02-01

To evaluate possible contribution of maturational delay of brain stem in the etiology of breath-holding spells in children using brain stem auditory evoked potentials. The study group included children who experienced breath-holding spells. The control group consisted of healthy age- and sex-matched children. Age, gender, type and frequency of spell, hemoglobin, and ferritin levels in study group and brain stem auditory evoked potentials results in both groups were recorded. Study group was statistically compared with control group for brain stem auditory evoked potentials. The mean age of study and control groups was 26.3 ± 14.6 and 28.9 ± 13.9 months, respectively. The III-V and I-V interpeak latencies were significantly prolonged in the study group compared with the control group (2.07 ± 0.2 milliseconds; 1.92 ± 0.13 milliseconds and 4.00 ± 0.27 milliseconds; 3.83 ± 0.19 milliseconds; P = 0.009 and P = 0.03, respectively). At the same time, III-V and I-V interpeak latencies of patients without anemia in the study group compared with those of control group were significantly prolonged (2.09 ± 0.24 milliseconds; 1.92 ± 0.13 milliseconds and 4.04 ± 0.28 milliseconds; 3.83 ± 0.19 milliseconds; P = 0.007 and P = 0.01, respectively). Our results consider that maturational delay in myelination of brain stem may have a role in the etiology of breath-holding spells in children.

Concise review: Patient-derived olfactory stem cells: new models for brain diseases.

PubMed

Mackay-Sim, Alan

2012-11-01

Traditional models of brain diseases have had limited success in driving candidate drugs into successful clinical translation. This has resulted in large international pharmaceutical companies moving out of neuroscience research. Cells are not brains, obviously, but new patient-derived stem models have the potential to elucidate cell biological aspects of brain diseases that are not present in worm, fly, or rodent models, the work horses of disease investigations and drug discovery. Neural stem cells are present in the olfactory mucosa, the organ of smell in the nose. Patient-derived olfactory mucosa has demonstrated disease-associated differences in a variety of brain diseases and recently olfactory mucosa stem cells have been generated from patients with schizophrenia, Parkinson's disease, and familial dysautonomia. By comparison with cells from healthy controls, patient-derived olfactory mucosa stem cells show disease-specific alterations in gene expression and cell functions including: a shorter cell cycle and faster proliferation in schizophrenia, oxidative stress in Parkinson's disease, and altered cell migration in familial dysautonomia. Olfactory stem cell cultures thus reveal patient-control differences, even in complex genetic diseases such as schizophrenia and Parkinson's disease, indicating that multiple genes of small effect can converge on shared cell signaling pathways to present as a disease-specific cellular phenotype. Olfactory mucosa stem cells can be maintained in homogeneous cultures that allow robust and repeatable multiwell assays suitable for screening libraries of drug candidate molecules. Copyright © 2012 AlphaMed Press.

Radial glia - from boring cables to stem cell stars.

PubMed

Malatesta, Paolo; Götz, Magdalena

2013-02-01

The discovery in the year 2000 that radial glial cells act as neural stem and progenitor cells in development has led to a change in the concept of neural stem cells in the adult brain. Not only are adult stem cells in the neurogenic niches glial in nature, but also glial cells outside these niches display greater potential when reacting to brain injury. Thus, a concept that emerged from developmental studies may hold the clue for neural repair.

The developmental origin of brain tumours: a cellular and molecular framework.

PubMed

Azzarelli, Roberta; Simons, Benjamin D; Philpott, Anna

2018-05-14

The development of the nervous system relies on the coordinated regulation of stem cell self-renewal and differentiation. The discovery that brain tumours contain a subpopulation of cells with stem/progenitor characteristics that are capable of sustaining tumour growth has emphasized the importance of understanding the cellular dynamics and the molecular pathways regulating neural stem cell behaviour. By focusing on recent work on glioma and medulloblastoma, we review how lineage tracing contributed to dissecting the embryonic origin of brain tumours and how lineage-specific mechanisms that regulate stem cell behaviour in the embryo may be subverted in cancer to achieve uncontrolled proliferation and suppression of differentiation. © 2018. Published by The Company of Biologists Ltd.

Characterization of TLX expression in neural stem cells and progenitor cells in adult brains.

PubMed

Li, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, Yanhong

2012-01-01

TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.

Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains

PubMed Central

Li, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, Yanhong

2012-01-01

TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression.Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells. PMID:22952666

Age-dependent redox status in the brain stem of NO-deficient hypertensive rats.

PubMed

Majzúnová, Miroslava; Pakanová, Zuzana; Kvasnička, Peter; Bališ, Peter; Čačányiová, Soňa; Dovinová, Ima

2017-09-11

The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/kg/day), a specific nNOS inhibitor, with N G -nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L-NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME- induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level.

Morphofunctional study of the therapeutic efficacy of human mesenchymal and neural stem cells in rats with diffuse brain injury.

PubMed

Tsyb, A F; Yuzhakov, V V; Roshal', L M; Sukhikh, G T; Konoplyannikov, A G; Sushkevich, G N; Yakovleva, N D; Ingel', I E; Bandurko, L N; Sevan'kaeva, L E; Mikhina, L N; Fomina, N K; Marei, M V; Semenova, Zh B; Konoplyannikova, O A; Kal'sina, S Sh; Lepekhina, L A; Semenkova, I V; Agaeva, E V; Shevchuk, A S; Pavlova, L N; Tokarev, O Yu; Karaseva, O V; Chernyshova, T A

2009-01-01

We studied the effect of transplantation of human stem cells from various tissues on reparative processes in the brain of rats with closed craniocerebral injury. Combined treatment with standard drugs and systemic administration of xenogeneic stem cells had a neuroprotective effect. The morphology of neurons rapidly returned to normal after administration of fetal neural stem cells. Fetal mesenchymal stem cells produced a prolonged effect on proliferative activity of progenitor cells in the subventricular zone of neurogenesis. Adult mesenchymal stem cells had a strong effect on recovery of the vascular bed in ischemic regions.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Viability and neuronal differentiation of neural stem cells encapsulated in silk fibroin hydrogel functionalized with an IKVAV peptide.

PubMed

Sun, Wei; Incitti, Tania; Migliaresi, Claudio; Quattrone, Alessandro; Casarosa, Simona; Motta, Antonella

2017-05-01

Three-dimensional (3D) porous scaffolds combined with therapeutic stem cells play vital roles in tissue engineering. The adult brain has very limited regeneration ability after injuries such as trauma and stroke. In this study, injectable 3D silk fibroin-based hydrogel scaffolds with encapsulated neural stem cells were developed, aiming at supporting brain regeneration. To improve the function of the hydrogel towards neural stem cells, silk fibroin was modified by an IKVAV peptide through covalent binding. Both unmodified and modified silk fibroin hydrogels were obtained, through sonication, with mechanical stiffness comparable to that of brain tissue. Human neural stem cells were encapsulated in both hydrogels and the effects of IKVAV peptide conjugation on cell viability and neural differentiation were assessed. The silk fibroin hydrogel modified by IKVAV peptide showed increased cell viability and an enhanced neuronal differentiation capability, which contributed to understanding the effects of IKVAV peptide on the behaviour of neural stem cells. For these reasons, IKVAV-modified silk fibroin is a promising material for brain tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Sex differences in the expression of estrogen receptor alpha within noradrenergic neurons in the sheep brain stem.

PubMed

Rose, J L; Hamlin, A S; Scott, C J

2014-10-01

In female sheep, high levels of estrogen exert a positive feedback action on gonadotropin releasing hormone (GnRH) secretion to stimulate a surge in luteinizing hormone (LH) secretion. Part of this action appears to be via brain stem noradrenergic neurons. By contrast, estrogen action in male sheep has a negative feedback action to inhibit GnRH and LH secretion. To investigate whether part of this sex difference is due to differences in estrogen action in the brain stem, we tested the hypothesis that the distribution of estrogen receptor α (ERα) within noradrenergic neurons in the brain stem differs between rams and ewes. To determine the distribution of ERα, we used double-label fluorescence immunohistochemistry for dopamine β-Hydroxylase, as a marker for noradrenergic and adrenergic cells, and ERα. In the ventrolateral medulla (A1 region), most ERα-immunoreactive (-ir) cells were located in the caudal part of the nucleus. Overall, there were more ERα-ir cells in rams than ewes, but the proportion of double-labeled cells was did not differ between sexes. Much greater numbers of ERα-ir cells were found in the nucleus of the solitary tract (A2 region), but <10% were double labeled and there were no sex differences. The majority of ERα-labeled cells in this nucleus was located in the more rostral areas. ERα-labeled cells were found in several rostral brain stem regions but none of these were double labeled and so were not quantified. Because there was no sex difference in the number of ERα-ir cells in the brain stem that were noradrenergic, the sex difference in the action of estrogen on gonadotropin secretion in sheep is unlikely to involve actions on brain stem noradrenergic cells. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Exposure to 835 MHz radiofrequency electromagnetic field induces autophagy in hippocampus but not in brain stem of mice.

PubMed

Kim, Ju Hwan; Yu, Da-Hyeon; Kim, Hyo-Jeong; Huh, Yang Hoon; Cho, Seong-Wan; Lee, Jin-Koo; Kim, Hyung-Gun; Kim, Hak Rim

2018-01-01

The exploding popularity of mobile phones and their close proximity to the brain when in use has raised public concern regarding possible adverse effects from exposure to radiofrequency electromagnetic fields (RF-EMF) on the central nervous system. Numerous studies have suggested that RF-EMF emitted by mobile phones can influence neuronal functions in the brain. Currently, there is still very limited information on what biological mechanisms influence neuronal cells of the brain. In the present study, we explored whether autophagy is triggered in the hippocampus or brain stem after RF-EMF exposure. C57BL/6 mice were exposed to 835 MHz RF-EMF with specific absorption rates (SAR) of 4.0 W/kg for 12 weeks; afterward, the hippocampus and brain stem of mice were dissected and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that several autophagic genes, which play key roles in autophagy regulation, were significantly upregulated only in the hippocampus and not in the brain stem. Expression levels of LC3B-II protein and p62, crucial autophagic regulatory proteins, were significantly changed only in the hippocampus. In parallel, transmission electron microscopy (TEM) revealed an increase in the number of autophagosomes and autolysosomes in the hippocampal neurons of RF-EMF-exposed mice. The present study revealed that autophagy was induced in the hippocampus, not in the brain stem, in 835 MHz RF-EMF with an SAR of 4.0 W/kg for 12 weeks. These results could suggest that among the various adaptation processes to the RF-EMF exposure environment, autophagic degradation is one possible mechanism in specific brain regions.

Moebius Syndrome

MedlinePlus

... by small or absent brain stem nuclei that control the cranial nerves; Group II, characterized by loss and degeneration of neurons ... by small or absent brain stem nuclei that control the cranial nerves; Group II, characterized by loss and degeneration of neurons ...

Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

PubMed Central

Swartling, Fredrik J.; Savov, Vasil; Persson, Anders I.; Chen, Justin; Hackett, Christopher S.; Northcott, Paul A.; Grimmer, Matthew R.; Lau, Jasmine; Chesler, Louis; Perry, Arie; Phillips, Joanna J.; Taylor, Michael D.; Weiss, William A.

2012-01-01

SUMMARY The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally-stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating SHH-dependence and SHH-independence, respectively. These differences were regulated in-part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. PMID:22624711

Control of abdominal muscles by brain stem respiratory neurons in the cat

NASA Technical Reports Server (NTRS)

Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

1985-01-01

The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

Organotypic slice cultures containing the preBötzinger complex generate respiratory-like rhythms

PubMed Central

Phillips, Wiktor S.; Herly, Mikkel; Del Negro, Christopher A.

2015-01-01

Study of acute brain stem slice preparations in vitro has advanced our understanding of the cellular and synaptic mechanisms of respiratory rhythm generation, but their inherent limitations preclude long-term manipulation and recording experiments. In the current study, we have developed an organotypic slice culture preparation containing the preBötzinger complex (preBötC), the core inspiratory rhythm generator of the ventrolateral brain stem. We measured bilateral synchronous network oscillations, using calcium-sensitive fluorescent dyes, in both ventrolateral (presumably the preBötC) and dorsomedial regions of slice cultures at 7–43 days in vitro. These calcium oscillations appear to be driven by periodic bursts of inspiratory neuronal activity, because whole cell recordings from ventrolateral neurons in culture revealed inspiratory-like drive potentials, and no oscillatory activity was detected from glial fibrillary associated protein-expressing astrocytes in cultures. Acute slices showed a burst frequency of 10.9 ± 4.2 bursts/min, which was not different from that of brain stem slice cultures (13.7 ± 10.6 bursts/min). However, slice cocultures that include two cerebellar explants placed along the dorsolateral border of the brainstem displayed up to 193% faster burst frequency (22.4 ± 8.3 bursts/min) and higher signal amplitude (340%) compared with acute slices. We conclude that preBötC-containing slice cultures retain inspiratory-like rhythmic function and therefore may facilitate lines of experimentation that involve extended incubation (e.g., genetic transfection or chronic drug exposure) while simultaneously being amenable to imaging and electrophysiology at cellular, synaptic, and network levels. PMID:26655824

The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells.

PubMed

Koyama-Nasu, R; Haruta, R; Nasu-Nishimura, Y; Taniue, K; Katou, Y; Shirahige, K; Todo, T; Ino, Y; Mukasa, A; Saito, N; Matsui, M; Takahashi, R; Hoshino-Okubo, A; Sugano, H; Manabe, E; Funato, K; Akiyama, T

2014-04-24

Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma.

Behavior of Xeno-Transplanted Undifferentiated Human Induced Pluripotent Stem Cells Is Impacted by Microenvironment Without Evidence of Tumors.

PubMed

Martínez-Cerdeño, Veronica; Barrilleaux, Bonnie L; McDonough, Ashley; Ariza, Jeanelle; Yuen, Benjamin T K; Somanath, Priyanka; Le, Catherine T; Steward, Craig; Horton-Sparks, Kayla; Knoepfler, Paul S

2017-10-01

Human pluripotent stem cells (hPSC) have great clinical potential through the use of their differentiated progeny, a population in which there is some concern over risks of tumorigenicity or other unwanted cellular behavior due to residual hPSC. Preclinical studies using human stem cells are most often performed within a xenotransplant context. In this study, we sought to measure how undifferentiated hPSC behave following xenotransplant. We directly transplanted undifferentiated human induced pluripotent stem cells (hIPSC) and human embryonic stem cells (hESC) into the adult mouse brain ventricle and analyzed their fates. No tumors or precancerous lesions were present at more than one year after transplantation. This result differed with the tumorigenic capacity we observed after allotransplantation of mouse ESC into the mouse brain. A substantial population of cellular derivatives of undifferentiated hESC and hIPSC engrafted, survived, and migrated within the mouse brain parenchyma. Within brain structures, transplanted cell distribution followed a very specific pattern, suggesting the existence of distinct microenvironments that offer different degrees of permissibility for engraftment. Most of the transplanted hESC and hIPSC that developed into brain cells were NeuN+ neuronal cells, and no astrocytes were detected. Substantial cell and nuclear fusion occurred between host and transplanted cells, a phenomenon influenced by microenvironment. Overall, hIPSC appear to be largely functionally equivalent to hESC in vivo. Altogether, these data bring new insights into the behavior of stem cells without prior differentiation following xenotransplantation into the adult brain.

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.

PubMed

Ahmed, Nabil; Salsman, Vita S; Kew, Yvonne; Shaffer, Donald; Powell, Suzanne; Zhang, Yi J; Grossman, Robert G; Heslop, Helen E; Gottschalk, Stephen

2010-01-15

Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor. The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-gamma and interleukin-2 in a HER2-dependent manner. Patients' HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of autologous GBM xenografts established in the brain of severe combined immunodeficient mice. Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T cells may be a promising immunotherapeutic approach for GBM.

Learning Disability Assessed through Audiologic and Physiologic Measures: A Case Study.

ERIC Educational Resources Information Center

Greenblatt, Edward R.; And Others

1983-01-01

The report describes a child with central auditory dysfunction, the first reported case where brain-stem dysfunction on audiologic tests were associated with specific electrophysiologic changes in the brain-stem auditory-evoked responses. (Author/CL)

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells.

PubMed

Silva, Patrícia Benites Gonçalves da; Rodini, Carolina Oliveira; Kaid, Carolini; Nakahata, Adriana Miti; Pereira, Márcia Cristina Leite; Matushita, Hamilton; Costa, Silvia Souza da; Okamoto, Oswaldo Keith

2016-08-01

Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

Experimental missile wound to the brain.

PubMed

Carey, M E; Sarna, G S; Farrell, J B; Happel, L T

1989-11-01

Among civilians in the United States, 33,000 gunshot wound deaths occur each year; probably half of these involve the head. In combat, head wounds account for approximately half of the immediate mortality when death can be attributed to a single wound. No significant reduction in the neurosurgical mortality associated with these wounds has occurred between World War II and the Vietnam conflict, and very little research into missile wounds of the brain has been undertaken. An experimental model has been developed in the anesthetized cat whereby a ballistic injury to the brain may be painlessly reproduced in order that the pathophysiological effects of brain wounding may be studied and better treatments may be designed to lower the mortality and morbidity rates associated with gunshot wounds. Prominent among physiological effects observed in this model was respiratory arrest even though the missile did not injure the brain stem directly. The incidence of prolonged respiratory arrest increased with increasing missile energy, but arrest was often reversible provided respiratory support was given. It is possible that humans who receive a brain wound die from missile-induced apnea instead of brain damage per se. The mortality rate in humans with brain wounding might be reduced by prompt respiratory support. Brain wounding was associated with persistently increased intracranial pressure and reduced cerebral perfusion pressure not entirely attributable to intracranial bleeding. The magnitude of these derangements appeared to be missile energy-dependent and approached dangerous levels in higher-energy wounds. All wounded cats exhibited postwounding increases in blood glucose concentrations consistent with a generalized stress reaction. A transient rise in hematocrit also occurred immediately after wounding. Both of these phenomena could prove deleterious to optimal brain function after injury.

Cell Therapy in Parkinson's Disease: Host Brain Repair Machinery Gets a Boost From Stem Cell Grafts.

PubMed

Napoli, Eleonora; Borlongan, Cesar V

2017-06-01

This commentary highlights the major findings and future research directions arising from the recent publication by Zuo and colleagues in Stem Cells 2017 (in press). Here, we discuss the novel observations that transplanted human neural stem cells can induce endogenous brain repair by specifically stimulating a host of regenerative processes in the neurogenic niche (i.e., subventricular zone [SVZ]) in an animal model of Parkinson's disease. That the identified therapeutic proteomes, neurotrophic factors, and anti-inflammatory cytokines in the SVZ may facilitate brain regeneration and behavioral recovery open a new venue of research for our understanding of the pathology and treatment of Parkinson's disease. Stem Cells 2017;35:1443-1445. © 2017 AlphaMed Press.

SU-E-T-493: Analysis of the Impact of Range and Setup Uncertainties On the Dose to Brain Stem and Whole Brain in the Passively Scattered Proton Therapy Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahoo, N; Zhu, X; Zhang, X

Purpose: To quantify the impact of range and setup uncertainties on various dosimetric indices that are used to assess normal tissue toxicities of patients receiving passive scattering proton beam therapy (PSPBT). Methods: Robust analysis of sample treatment plans of six brain cancer patients treated with PSPBT at our facility for whom the maximum brain stem dose exceeded 5800 CcGE were performed. The DVH of each plan was calculated in an Eclipse treatment planning system (TPS) version 11 applying ±3.5% range uncertainty and ±3 mm shift of the isocenter in x, y and z directions to account for setup uncertainties. Worst-casemore » dose indices for brain stem and whole brain were compared to their values in the nominal plan to determine the average change in their values. For the brain stem, maximum dose to 1 cc of volume, dose to 10%, 50%, 90% of volume (D10, D50, D90) and volume receiving 6000, 5400, 5000, 4500, 4000 CcGE (V60, V54, V50, V45, V40) were evaluated. For the whole brain, maximum dose to 1 cc of volume, and volume receiving 5400, 5000, 4500, 4000, 3000 CcGE (V54, V50, V45, V40 and V30) were assessed. Results: The average change in the values of these indices in the worst scenario cases from the nominal plan were as follows. Brain stem; Maximum dose to 1 cc of volume: 1.1%, D10: 1.4%, D50: 8.0%, D90:73.3%, V60:116.9%, V54:27.7%, V50: 21.2%, V45:16.2%, V40:13.6%,Whole brain; Maximum dose to 1 cc of volume: 0.3%, V54:11.4%, V50: 13.0%, V45:13.6%, V40:14.1%, V30:13.5%. Conclusion: Large to modest changes in the dosiemtric indices for brain stem and whole brain compared to nominal plan due to range and set up uncertainties were observed. Such potential changes should be taken into account while using any dosimetric parameters for outcome evaluation of patients receiving proton therapy.« less

The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment.

PubMed

Donega, Vanessa; van Velthoven, Cindy T J; Nijboer, Cora H; Kavelaars, Annemieke; Heijnen, Cobi J

2013-05-01

Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody.

PubMed

Barnett, M; Prosser, J; Sutton, I; Halmagyi, G M; Davies, L; Harper, C; Dalmau, J

2001-02-01

A woman developed brain stem encephalopathy in association with serum anti-Ma2 antibodies and left upper lobe lung mass. T2 weighted MRI of the brain showed abnormalities involving the pons, left middle and superior cerebellar peduncles, and bilateral basal ganglia. Immunohistochemical analysis for serum antineuronal antibodies was confounded by the presence of a non-neuronal specific antinuclear antibody. Immunoblot studies showed the presence of anti-Ma2 antibodies. A premortem tissue diagnosis of the lung mass could not be established despite two CT guided needle biopsies, and the patient died as a result of rapid neurological deterioration. The necropsy showed that the lung lesion was an adenocarcinoma which expressed Ma2 immunoreactive protein. Neuropathological findings included prominent perivascular inflammatory infiltrates, glial nodules, and neuronophagia involving the brain stem, basal ganglia, hippocampus and the dentate nucleus of the cerebellum. Ma2 is an autoantigen previously identified in patients with germ cell tumours of the testis and paraneoplastic brain stem and limbic encephalitis. Our patient's clinical and immunopathological findings indicate that this disorder can affect women with lung adenocarcinoma, and that the encephalitic changes predominate in those regions of the brain known to express high concentrations of Ma proteins.

Expression and function of orphan nuclear receptor TLX in adult neural stem cells.

PubMed

Shi, Yanhong; Chichung Lie, D; Taupin, Philippe; Nakashima, Kinichi; Ray, Jasodhara; Yu, Ruth T; Gage, Fred H; Evans, Ronald M

2004-01-01

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.

Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody

PubMed Central

Barnett, M; Prosser, J; Sutton, I; Halmagyi, G; Davies, L; Harper, C; Dalmau, J

2001-01-01

A woman developed brain stem encephalopathy in association with serum anti-Ma2 antibodies and left upper lobe lung mass. T2 weighted MRI of the brain showed abnormalities involving the pons, left middle and superior cerebellar peduncles, and bilateral basal ganglia. Immunohistochemical analysis for serum antineuronal antibodies was confounded by the presence of a non-neuronal specific antinuclear antibody. Immunoblot studies showed the presence of anti-Ma2 antibodies. A premortem tissue diagnosis of the lung mass could not be established despite two CT guided needle biopsies, and the patient died as a result of rapid neurological deterioration. The necropsy showed that the lung lesion was an adenocarcinoma which expressed Ma2 immunoreactive protein. Neuropathological findings included prominent perivascular inflammatory infiltrates, glial nodules, and neuronophagia involving the brain stem, basal ganglia, hippocampus and the dentate nucleus of the cerebellum. Ma2 is an autoantigen previously identified in patients with germ cell tumours of the testis and paraneoplastic brain stem and limbic encephalitis. Our patient's clinical and immunopathological findings indicate that this disorder can affect women with lung adenocarcinoma, and that the encephalitic changes predominate in those regions of the brain known to express high concentrations of Ma proteins.

 PMID:11160472

Adult neural stem cells: The promise of the future

PubMed Central

Taupin, Philippe

2007-01-01

Stem cells are self-renewing undifferentiated cells that give rise to multiple types of specialized cells of the body. In the adult, stem cells are multipotents and contribute to homeostasis of the tissues and regeneration after injury. Until recently, it was believed that the adult brain was devoid of stem cells, hence unable to make new neurons and regenerate. With the recent evidences that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS), the adult brain has the potential to regenerate and may be amenable to repair. The function(s) of NSCs in the adult CNS remains the source of intense research and debates. The promise of the future of adult NSCs is to redefine the functioning and physiopathology of the CNS, as well as to treat a broad range of CNS diseases and injuries. PMID:19300610

Bioreactivity: Studies on a Simple Brain Stem Reflex in Behaving Animals

DTIC Science & Technology

1988-07-22

neuromodulation , or complex behavioral processes, such as arousal, is finding a simple system that will permit such analyses. The brain stem...systems important in neuromodulation and arousal. Initial pharmacologic studies showed that locally applied norepinephrine facilitated the reflex

Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma

ClinicalTrials.gov

2017-10-11

Brain Stem Glioma; Cerebral Astrocytoma; Childhood Cerebellar Anaplastic Astrocytoma; Childhood Cerebral Anaplastic Astrocytoma; Childhood Spinal Cord Neoplasm; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebral Astrocytoma

[Are subcortical signs in the EEG a reliable indication of brain stem displacement and impaction processes by intracranial space-occupying processes? A comparative computer tomography-electroencephalography study].

PubMed

Zettler, H; Järisch, M; Leonhard, T

1985-01-01

Within the scope of an elektroencephalographic-computertomographic comperative study carried out in 430 patients, the concurrence of secondary brain stem damage due to mass displacement and herniation processes and parroxysmal generalised slow activity in the EEG ("intermittant frontal delta rhythms", "projected discharges", "subcortical signs") in intracranial space-occupying processes were studied among others. The occurrence of the EEG pattern was independent of the presence of brain stem displacements in about 20 and 25 per cent, respectively, of the 152 patients with supratentorial space occupations. The absence of the characteristics on 80 per cent of the patients with clear CT criteria for a secondary brain stem impairment shows that it is not suitable as a warning sign of an imminent intracranial decompensation and that in particular from the non-occurrence in the EEG no contribution to the operative risk and to the choice of the time of the operation can be derived. A relation between the occurrence of paroxysmal slow activity and the acuity of the course of the disease or the degree of malignity of cerebral tumours could not be verified. Possible causes of the inconstant occurrence of this EEG pattern in brain stem alterations are discussed.

Effects of neuroinflammation on the regenerative capacity of brain stem cells.

PubMed

Russo, Isabella; Barlati, Sergio; Bosetti, Francesca

2011-03-01

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the lipopolysaccharide-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Human Cytomegalovirus IE2 Protein Disturbs Brain Development by the Dysregulation of Neural Stem Cell Maintenance and the Polarization of Migrating Neurons.

PubMed

Han, Dasol; Byun, Sung-Hyun; Kim, Juwan; Kwon, Mookwang; Pleasure, Samuel J; Ahn, Jin-Hyun; Yoon, Keejung

2017-09-01

Despite the high incidence of severe defects in the central nervous system caused by human cytomegalovirus (HCMV) congenital infection, the mechanism of HCMV neuropathogenesis and the roles of individual viral genes have not yet been fully determined. In this study, we show that the immediate-early 2 (IE2) protein may play a key role in HCMV-caused neurodevelopmental disorders. IE2-transduced neural progenitor cells gave rise to neurospheres with a lower frequency and produced smaller neurospheres than control cells in vitro , indicating reduction of self-renewal and expansion of neural progenitors by IE2. At 2 days after in utero electroporation into the ventricle of the developing brain, a dramatically lower percentage of IE2-expressing cells was detected in the ventricular zone (VZ) and cortical plate (CP) compared to control cells, suggesting that IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP. In addition, most IE2 + cells in the lower intermediate zone either showed multipolar morphology with short neurites or possessed nonradially oriented processes, whereas control cells had long, radially oriented monopolar or bipolar neurites. IE2 + callosal axons also failed to cross the midline to form the corpus callosum. Furthermore, we provide molecular evidence that the cell cycle arrest and DNA binding activities of IE2 appear to be responsible for the increased neural stem cell exit from the VZ and cortical migrational defects, respectively. Collectively, our results demonstrate that IE2 disrupts the orderly process of brain development in a stepwise manner to further our understanding of neurodevelopmental HCMV pathogenesis. IMPORTANCE HCMV brain pathogenesis has been studied in limited experimental settings, such as in vitro HCMV infection of neural progenitor cells or in vivo murine CMV infection of the mouse brain. Here, we show that IE2 is a pivotal factor that contributes to HCMV-induced abnormalities in the context of the embryonic brain using an in utero gene transfer tool. Surprisingly, IE2, but not HCMV IE1 or murine CMV ie3, interferes pleiotropically with key neurodevelopmental processes, including neural stem cell regulation, proper positioning of migrating neurons, and the callosal axon projections important for communication between the hemispheres. Our data suggest that the wide spectrum of clinical outcomes, ranging from mental retardation to microcephaly, caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone. Copyright © 2017 American Society for Microbiology.

Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signalling cascade in the vertebrate adult brain.

PubMed

Than-Trong, Emmanuel; Ortica-Gatti, Sara; Mella, Sébastien; Nepal, Chirag; Alunni, Alessandro; Bally-Cuif, Laure

2018-05-15

Neural stem cells (NSCs) in the adult vertebrate brain are found in a quiescent state and can preserve long-lasting progenitor potential (stemness). Whether and how these two properties are linked, and to what extent they can be independently controlled by NSC maintenance pathways, is unresolved. We have previously identified Notch3 signalling as a major quiescence-promoting pathway in adult NSCs of the zebrafish pallium. We now show that Notch3 also controls NSC stemness. Using parallel transcriptomic characterizations of notch3 mutant NSCs and adult NSC physiological states, we demonstrate that a set of potentially direct Notch3 target genes distinguishes quiescence and stemness control. As a proof of principle, we focus on one 'stemness' target, encoding the bHLH transcription factor Hey1, that has not yet been analysed in adult NSCs. We show that abrogation of Hey1 function in adult pallial NSCs in vivo , including quiescent NSCs, leads to their differentiation without affecting their proliferation state. These results demonstrate that quiescence and stemness are molecularly distinct outputs of Notch3 signalling, and identify Hey1 as a major Notch3 effector controlling NSC stemness in the vertebrate adult brain. © 2018. Published by The Company of Biologists Ltd.

Analysis of Neural Stem Cells from Human Cortical Brain Structures In Vitro.

PubMed

Aleksandrova, M A; Poltavtseva, R A; Marei, M V; Sukhikh, G T

2016-05-01

Comparative immunohistochemical analysis of the neocortex from human fetuses showed that neural stem and progenitor cells are present in the brain throughout the gestation period, at least from week 8 through 26. At the same time, neural stem cells from the first and second trimester fetuses differed by the distribution, morphology, growth, and quantity. Immunocytochemical analysis of neural stem cells derived from fetuses at different gestation terms and cultured under different conditions showed their differentiation capacity. Detailed analysis of neural stem cell populations derived from fetuses on gestation weeks 8-9, 18-20, and 26 expressing Lex/SSEA1 was performed.

Neural conduction abnormality in the brain stem and prevalence of the abnormality in late preterm infants with perinatal problems.

PubMed

Jiang, Ze Dong

2013-08-01

Neurodevelopment in late preterm infants has recently attracted considerable interest. The prevalence of brain stem conduction abnormality remains unknown. We examined maximum length sequence brain stem auditory evoked response in 163 infants, born at 33-36 weeks gestation, who had various perinatal problems. Compared with 49 normal term infants without problems, the late preterm infants showed a significant increase in III-V and I-V interpeak intervals at all 91-910/s clicks, particularly at 455 and 910/s (p < 0.01-0.001). The I-III interval was slightly increased, without statistically significant difference from the controls at any click rates. These results suggest that neural conduction along the, mainly more central or rostral part of, auditory brain stem is abnormal in late preterm infants with perinatal problems. Of the 163 late preterm infant, the number (and percentage rate) of infants with abnormal I-V interval at 91, 227, 455, and 910/s clicks was, respectively, 11 (6.5%), 17 (10.2%), 37 (22.3%), and 31 (18.7%). The number (and percentage rate) of infants with abnormal III-V interval at these rates was, respectively, 10 (6.0%), 17 (10.2%), 28 (16.9), and 36 (21.2%). Apparently, the abnormal rates were much higher at 455 and 910/s clicks than at lower rates 91 and 227/s. In total, 42 (25.8%) infants showed abnormal I-V and/or III-V intervals. Conduction in, mainly in the more central part, the brain stem is abnormal in late preterm infants with perinatal problems. The abnormality is more detectable at high- than at low-rate sensory stimulation. A quarter of late preterm infants with perinatal problems have brain stem conduction abnormality.

Altered states of consciousness in epilepsy: a DTI study of the brain.

PubMed

Xie, Fangfang; Xing, Wu; Wang, Xiaoyi; Liao, Weihua; Shi, Wei

2017-08-01

A disturbance in the level of consciousness is a classical clinical sign of several seizure types. Recent studies have shown that altered states of consciousness in seizures are associated with structural and functional changes of several brain regions. Prominent among these are the thalamus, the brain stem and the default mode network, which is part of the consciousness system. Our study used diffusion tensor imaging (DTI) to evaluate these brain regions in patients with three different types of epilepsies that are associated with altered consciousness: complex partial seizures (CPS), primary generalized tonic-clonic seizures (PGTCS) or secondary generalized tonic-clonic seizures (SGTCS). Additionally, this study further explores the probable mechanisms underlying impairment of consciousness in seizures. Conventional MRI and DTI scanning were performed in 51 patients with epilepsy and 51 healthy volunteers. The epilepsy group was in turn subdivided into three subgroups: CPS, PGTCS or SGTCS. Each subgroup comprised 17 patients. Each subject involved in the study underwent a DTI evaluation of the brain to measure the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of nine regions of interest: the postero-superior portion of midbrain, the bilateral dorsal thalamus, the bilateral precuneus/posterior cingulate, the bilateral medial pre-frontal gyri and the bilateral supramarginalgyri. The statistical significance of the measured ADC and FA values between the experimental and control groups was analysed using the paired t-test, and one-way analysis of variance was performed for a comparative analysis between the three subgroups. Statistically significantly higher ADC values ( p < 0.01) were observed in the bilateral dorsal thalamus and postero-superior aspect of the midbrain in the three patient subgroups than in the control group. There were no significant changes in the ADC values ( p > 0.05) in the bilateral precuneus/posterior cingulate, bilateral medial pre-frontal gyri or bilateral supramarginalgyri in the experimental group. Among the three patient subgroups and the ADC values of corresponding brain regions, there were no statistically significant changes. Statistically significantly lower FA values ( p < 0.05) were observed in the bilateral dorsal thalamus of the patients in the three subgroups than in the control group. Significantly lowered FA values from the postero-superior aspect of the mid brain ( p < 0.01) were observed in patients with PGTCS compared with the control group. There were no significant changes in the FA values ( p > 0.05) from the bilateral precuneus/posterior cingulate, bilateral medial frontal gyri or bilateral supramarginalgyri in the experimental group. Among the three patient subgroups and the FA values of the corresponding brain regions, there were no statistically significant changes. In epileptic patients with CPS, PGTCS or SGTCS, there seems to be a long-lasting neuronal dysfunction of the bilateral dorsal thalamus and postero-superior aspect of the midbrain. The thalamus and upper brain stem are likely to play a key role in epileptic patients with impaired consciousness.

Human adipose-derived stem cells ameliorate repetitive behavior, social deficit and anxiety in a VPA-induced autism mouse model.

PubMed

Ha, Sungji; Park, Hyunjun; Mahmood, Usman; Ra, Jeong Chan; Suh, Yoo-Hun; Chang, Keun-A

2017-01-15

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication, and patients often display co-occurring repetitive behaviors. Although the global prevalence of ASD has increased over time, the etiology and treatments for ASD are poorly understood. Recently, some researchers have suggested that stem cells have therapeutic potential for ASD. Thus, in the present study, we investigated the therapeutic effects of human adipose-derived stem cells (hASCs), a kind of autologous mesenchymal stem cells (MSCs) isolated from adipose tissue, on valproic acid (VPA)-induced autism model mice. Human ASCs were injected into the neonatal pups (P2 or P3) intraventricularly and then we evaluated major behavior symptoms of ASD. VPA-treated mice showed increased repetitive behaviors, decreased social interactions and increased anxiety but these autistic behaviors were ameliorated through transplantation of hASCs. In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice. The decreased level of vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10) by VPA were rescued in the brains of the hASC-injected VPA mice. With these results, we experimentally found hASCs' therapeutic effects on autistic phenotypes in a ASD model mice for the first time. This animal model system can be used to elucidate further mechanisms of therapeutic effects of hASCs in ASD. Copyright © 2016 Elsevier B.V. All rights reserved.

Stereotaxic gamma knife surgery in treatment of critically located pilocytic astrocytoma: preliminary result

PubMed Central

Hafez, Raef FA

2007-01-01

Background Low-grade gliomas are uncommon primary brain tumors, located more often in the posterior fossa, optic pathway, and brain stem and less commonly in the cerebral hemispheres. Case presentations Two patients with diagnosed recurrent cystic pilocytic astrocytoma critically located within the brain (thalamic and brain stem) were treated with gamma knife surgery. Gamma knife surgery (GKS) did improve the patient's clinical condition very much which remained stable later on. Progressive reduction on the magnetic resonance imaging (MRI) studies of the solid part of the tumor and almost disappearance of the cystic component was achieved within the follow-up period of 36 months in the first case with the (thalamic located lesion) and 22 months in the second case with the (brain stem located lesion). Conclusion Gamma knife surgery represents an alternate tool in the treatment of recurrent and/or small postoperative residual pilocytic astrocytoma especially if they are critically located PMID:17394660

Magnetic Resonance Imaging of Malformations of Midbrain-Hindbrain.

PubMed

Abdel Razek, Ahmed Abdel Khalek; Castillo, Mauricio

2016-01-01

We aim to review the magnetic resonance imaging appearance of malformations of midbrain and hindbrain. These can be classified as predominantly cerebellar malformations, combined cerebellar and brain stem malformations, and predominantly brain stem malformations. The diagnostic criteria for the majority of these morphological malformations are based on neuroimaging findings. The predominantly cerebellar malformations include predominantly vermian hypoplasia seen in Dandy-Walker malformation and rhombencephalosynapsis, global cerebellar hypoplasia reported in lissencephaly and microlissencephaly, and unilateral cerebellar hypoplasia seen in PHACES, vanishing cerebellum, and cerebellar cleft. Cerebellar dysplasias are seen in Chudley-McCullough syndrome, associated with LAMA1 mutations and GPR56 mutations; Lhermitte-Duclos disease; and focal cerebellar dysplasias. Cerebellar hyperplasias are seen in megalencephaly-related syndromes and hemimegalencephaly with ipsilateral cerebellomegaly. Cerebellar and brain stem malformations include tubulinopathies, Joubert syndrome, cobblestone malformations, pontocerebellar hypoplasias, and congenital disorders of glycosylation type Ia. Predominantly brain stem malformations include congenital innervation dysgenesis syndrome, pontine tegmental cap dysplasia, diencephalic-mesencephalic junction dysplasia, disconnection syndrome, and pontine clefts.

Continuous myocloni and tonic spasms in a 2-month-old infant with enterovirus 71 brain stem encephalitis.

PubMed

Lee, Kyung Yeon; Yeh, Hye-Ryun

2015-02-01

Brain stem encephalitis is a cardinal presentation of central nervous system involvement in enterovirus 71 infection, and manifests as myoclonus, ataxia, tremor, and autonomic dysfunction. A 2-month-old infant with enterovirus 71 brain stem encephalitis demonstrated continuous myocloni and tonic spasms. On admission, the patient's myoclonus, which mainly involved the shoulders and the arms, was considerably worse during wakefulness and occurred once or twice a minute. Several hours after admission, the myoclonic jerks steadily worsened, appeared ceaselessly every 1 to 2 seconds, and were intermixed with tonic spasms of all four extremities accompanied by crying. Video electroencephalography revealed a normal background without epileptiform discharges and no ictal electroencephalographic changes during the myoclonic jerks and tonic spasms. Complete remission was achieved without complications after completion of a 3-day immunoglobulin therapy. This case suggests that the brain stem may be a major origin site for not only myoclonus but also tonic spasm. Georg Thieme Verlag KG Stuttgart · New York.

Regional and stage-specific effects of prospectively purified vascular cells on the adult V-SVZ neural stem cell lineage.

PubMed

Crouch, Elizabeth E; Liu, Chang; Silva-Vargas, Violeta; Doetsch, Fiona

2015-03-18

Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic (V-SVZ) and non-neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions differentially promote the proliferation and neuronal differentiation of qNSCs, aNSCs, and TACs. Unexpectedly, diffusible cortical signals had the most potent effects on V-SVZ proliferation and neurogenesis, highlighting the intrinsic capacity of non-neurogenic vasculature to support stem cell behavior. Finally, we identify PlGF-2 as an endothelial-derived mitogen that promotes V-SVZ cell proliferation. This purification strategy provides a platform to define the functional and molecular contribution of vascular cells to stem cell niches and other brain regions under different physiological and pathological states. Copyright © 2015 the authors 0270-6474/15/354528-12$15.00/0.

Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells

PubMed Central

Golebiewska, Anna; Bougnaud, Sébastien; Stieber, Daniel; Brons, Nicolaas H. C.; Vallar, Laurent; Hertel, Frank; Klink, Barbara; Schröck, Evelin; Bjerkvig, Rolf

2013-01-01

The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the ‘side population’ phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours. PMID:23460667

[Immunohistochemical studies on neuronal changes in brain stem nucleus of forensic autopsied cases. I. Various cases of asphyxia and respiratory disorder].

PubMed

Kubo, S; Orihara, Y; Gotohda, T; Tokunaga, I; Tsuda, R; Ikematsu, K; Kitamura, O; Yamamoto, A; Nakasono, I

1998-12-01

Several nuclei in brain stem are well known to play an important role in supporting human life. However, the connection between neural changes of brain stem and the cause of death is not yet fully understood. To investigate the correlation of brain stem damage with various cause of respiratory disorders, neural changes of the arcuate nucleus (ARC), the hypoglossal nucleus (HN) and the inferior olivary nucleus (IO) were examined using immunohistochemical technique. Based on the cause of death, the forensic autopsy cases were divided into 5 groups as follows. Group I: hanging, ligature strangulation and manual strangulation, Group II: smothering and choking, Group III: drowning, Group IV: respiratory failure, control group: heat stroke and sun stroke. Brain was fixed with phosphate-buffer formalin, and the brain stem was horizontally dissected at the level of apex, then embedded in paraffin. The sections were stained with the antibodies against microtubule-associated protein 2 (MAP2), muscalinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock protein (HSP70). Three nuclei showed no obvious morphological changes in all examined groups. However, in case of asphyxia (Group I to III), neurons in HN were positively stained with both HSP70 and c-Fos antibodies. This may indicate that the occlusion of upper airway results in the neuronal damage of HN without their morphological changes. Positive staining of HSP70 and c-Fos in IO was more frequently observed in Group III than other 4 groups. Since IO is involved in maintaining body balance which is often disturbed by drowning, it seems possible that neuronal damage in IO observed in drowning may be related to the disturbance of body balance. These observations indicate that immunohistochemical study on the damage to neurons in brain stem nuclei can provide useful information for determining the cause of death.

Neural stem cells and neuro/gliogenesis in the central nervous system: understanding the structural and functional plasticity of the developing, mature, and diseased brain.

PubMed

Yamaguchi, Masahiro; Seki, Tatsunori; Imayoshi, Itaru; Tamamaki, Nobuaki; Hayashi, Yoshitaka; Tatebayashi, Yoshitaka; Hitoshi, Seiji

2016-05-01

Neurons and glia in the central nervous system (CNS) originate from neural stem cells (NSCs). Knowledge of the mechanisms of neuro/gliogenesis from NSCs is fundamental to our understanding of how complex brain architecture and function develop. NSCs are present not only in the developing brain but also in the mature brain in adults. Adult neurogenesis likely provides remarkable plasticity to the mature brain. In addition, recent progress in basic research in mental disorders suggests an etiological link with impaired neuro/gliogenesis in particular brain regions. Here, we review the recent progress and discuss future directions in stem cell and neuro/gliogenesis biology by introducing several topics presented at a joint meeting of the Japanese Association of Anatomists and the Physiological Society of Japan in 2015. Collectively, these topics indicated that neuro/gliogenesis from NSCs is a common event occurring in many brain regions at various ages in animals. Given that significant structural and functional changes in cells and neural networks are accompanied by neuro/gliogenesis from NSCs and the integration of newly generated cells into the network, stem cell and neuro/gliogenesis biology provides a good platform from which to develop an integrated understanding of the structural and functional plasticity that underlies the development of the CNS, its remodeling in adulthood, and the recovery from diseases that affect it.

Brain stem auditory evoked responses in human infants and adults

NASA Technical Reports Server (NTRS)

Hecox, K.; Galambos, R.

1974-01-01

Brain stem evoked potentials were recorded by conventional scalp electrodes in infants (3 weeks to 3 years of age) and adults. The latency of one of the major response components (wave V) is shown to be a function both of click intensity and the age of the subject; this latency at a given signal strength shortens postnatally to reach the adult value (about 6 msec) by 12 to 18 months of age. The demonstrated reliability and limited variability of these brain stem electrophysiological responses provide the basis for an optimistic estimate of their usefulness as an objective method for assessing hearing in infants and adults.

Tracking stem cell migration and survival in brain injury: current approaches and future prospects.

PubMed

Darkazalli, Ali; Levenson, Cathy W

2012-10-01

In recent years, stem cell-mediated therapies have gained considerable ground as potential treatments for a wide variety of brain pathologies including traumatic brain injury, stroke and neurodegenerative diseases. Despite extensive preclinical studies, many of these therapies have not been fully translated into viable clinical approaches. This is partly due to our inability to reliably track and monitor transplanted stem cells longitudinally over long periods of time in vivo. In this review, we discuss the predominant histological cell tracing methodologies, such as immunohistochemistry, and fluorescent cellular dyes and proteins, and compare them to emerging cellular imaging technologies. We show that advances in magnetic resonance imaging (MRI) have resulted in opportunities to use this technology to further our understanding of stem cell characteristics and behaviors in vivo. While MRI may not completely replace conventional cell tracking methods in pre-clinical, mechanistic work, it is clear that it has the potential to function as a powerful diagnostic tool for tracking stem cell migration and survival as well as for evaluating the efficacy of stem cell-mediated therapies.

Increased circulating stem cells and better cognitive performance in traumatic brain injury subjects following hyperbaric oxygen therapy.

PubMed

Shandley, Sabrina; Wolf, E George; Schubert-Kappan, Christine M; Baugh, Laura M; Richards, Michael F; Prye, Jennifer; Arizpe, Helen M; Kalns, John

2017-01-01

Traumatic brain injury (TBI) may cause persistent cognitive dysfunction. A pilot clinical study was performed to determine if hyperbaric oxygen (HBO₂) treatment improves cognitive performance. It was hypothesized that stem cells, mobilized by HBO₂ treatment, are recruited to repair damaged neuronal tissue. This hypothesis was tested by measuring the relative abundance of stem cells in peripheral blood and cognitive performance during this clinical trial. The subject population consisted of 28 subjects with persistent cognitive impairment caused by mild to moderate TBI suffered during military deployment to Iraq or Afghanistan. Fluorescence-activated cell sorting (FACS) analysis was performed for stem cell markers in peripheral blood and correlated with variables resulting from standard tests of cognitive performance and post-traumatic stress disorder: ImPACT, BrainCheckers and PCL-M test results. HBO₂ treatment correlated with stem cell mobilization as well as increased cognitive performance. Together these results support the hypothesis that stem cell mobilization may be required for cognitive improvement in this population. Copyright© Undersea and Hyperbaric Medical Society.

Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signalling cascade in the vertebrate adult brain

PubMed Central

Than-Trong, Emmanuel; Ortica-Gatti, Sara; Mella, Sébastien; Nepal, Chirag; Alunni, Alessandro

2018-01-01

ABSTRACT Neural stem cells (NSCs) in the adult vertebrate brain are found in a quiescent state and can preserve long-lasting progenitor potential (stemness). Whether and how these two properties are linked, and to what extent they can be independently controlled by NSC maintenance pathways, is unresolved. We have previously identified Notch3 signalling as a major quiescence-promoting pathway in adult NSCs of the zebrafish pallium. We now show that Notch3 also controls NSC stemness. Using parallel transcriptomic characterizations of notch3 mutant NSCs and adult NSC physiological states, we demonstrate that a set of potentially direct Notch3 target genes distinguishes quiescence and stemness control. As a proof of principle, we focus on one ‘stemness’ target, encoding the bHLH transcription factor Hey1, that has not yet been analysed in adult NSCs. We show that abrogation of Hey1 function in adult pallial NSCs in vivo, including quiescent NSCs, leads to their differentiation without affecting their proliferation state. These results demonstrate that quiescence and stemness are molecularly distinct outputs of Notch3 signalling, and identify Hey1 as a major Notch3 effector controlling NSC stemness in the vertebrate adult brain. PMID:29695612

Vorinostat and Radiation Therapy Followed by Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ClinicalTrials.gov

2018-06-19

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Brain Stem Glioma; Childhood Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Gliosarcoma

Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

ClinicalTrials.gov

2018-03-30

Anaplastic Astrocytoma; Brain Stem Glioma; Childhood Mixed Glioma; Fibrillary Astrocytoma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

The pattern of thalamocortical and brain stem projections to the vibrissae-related sensory and motor cortices in de-whiskered congenital hypothyroid rats.

PubMed

Afarinesh, Mohammad Reza; Behzadi, Gila

2017-08-01

The present study is designed to investigate the plastic organization of the thalamo-cortical (TC) and brain stem afferents of whisker primary sensory (wS1) and motor (wM1) cortical areas in congenital hypothyroid (CH) pups following whisker deprivation (WD) from neonatal to adolescence period. Maternal hypothyroidism was induced by adding propylthiouracil (PTU) to the drinking water from early embryonic day 16 to postnatal day (PND) 60. Pregnant rats were divided into intact and CH groups (n = 8). In each group, the total whiskers of pups (4 of 8) were trimmed continuously from PND 1 to PND 60. Retrograde tracing technique with WGA-HRP was performed in the present study. Retrogradely labeled neurons were observed in the specific thalamic nuclei (VPM and VL) following separately WGA-HRP injections into wS1/M1 cortical areas. The number of labeled cells in the VPM, VL, VM and PO nuclei of the thalamus significantly decreased in CH offsprings rats (P < 0.05). Neonatal WD did not show any significant effects on the number of VPM, VL, VM and PO labeled projection neurons to wS1 and wM1 cortical areas. In addition, retrogradely labeled neurons in dorsal raphe (DR) and locus coeruleus (LC) nuclei were observed in all experimental groups. The number of DR and LC labeled neurons were higher in the CH and whisker deprived groups compared to their matching controls (P < 0.05). Upon our results, CH and WD had no synergic or additive effects on the TC and brain stem afferent patterns of barrel sensory and motor cortices.

Music modulation of pain perception and pain-related activity in the brain, brain stem, and spinal cord: a functional magnetic resonance imaging study.

PubMed

Dobek, Christine E; Beynon, Michaela E; Bosma, Rachael L; Stroman, Patrick W

2014-10-01

The oldest known method for relieving pain is music, and yet, to date, the underlying neural mechanisms have not been studied. Here, we investigate these neural mechanisms by applying a well-defined painful stimulus while participants listened to their favorite music or to no music. Neural responses in the brain, brain stem, and spinal cord were mapped with functional magnetic resonance imaging spanning the cortex, brain stem, and spinal cord. Subjective pain ratings were observed to be significantly lower when pain was administered with music than without music. The pain stimulus without music elicited neural activity in brain regions that are consistent with previous studies. Brain regions associated with pleasurable music listening included limbic, frontal, and auditory regions, when comparing music to non-music pain conditions. In addition, regions demonstrated activity indicative of descending pain modulation when contrasting the 2 conditions. These regions include the dorsolateral prefrontal cortex, periaqueductal gray matter, rostral ventromedial medulla, and dorsal gray matter of the spinal cord. This is the first imaging study to characterize the neural response of pain and how pain is mitigated by music, and it provides new insights into the neural mechanism of music-induced analgesia within the central nervous system. This article presents the first investigation of neural processes underlying music analgesia in human participants. Music modulates pain responses in the brain, brain stem, and spinal cord, and neural activity changes are consistent with engagement of the descending analgesia system. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Surgical management of brain-stem cavernous malformations: report of 137 cases.

PubMed

Wang, Chung-cheng; Liu, Ali; Zhang, Jun-ting; Sun, Bo; Zhao, Yuan-li

2003-06-01

With the improvement in neuroimaging and microsurgical techniques, brain stem cavernous malformations are no longer considered inoperable. Surgical indications for brainstem cavernoma are evolving, with better understanding of its natural history and decreasing surgical complications. During 1986 through 1998, a series of 137 patients (4 patients each with two brain stem lesions, total number of lesions, 141) with brain stem cavernous malformations were treated microsurgically at Beijing Neurosurgery Institute. The age distribution, lesion location, and clinical presentations were analyzed. The bleeding rate, surgical indications and microsurgical techniques were also discussed. In our series, 92 of 137 cases (67.2%) suffered more than one hemorrhage. Female patients had a higher risk of recurrent hemorrhage than that of male patients. Unlike cavernomas malformations from other locations, repeated hemorrhages from brain stem malformations are much more common and usually lead to new neurologic deficits. Among all 137 surgically treated patients, there was no operative mortality. Ninety-nine patients (72.3%) either improved or remained clinically stable postoperatively. The size of the cavernoma/hematoma does not necessarily correlate with the surgical result. While the acute hematoma can facilitate the surgical dissection, longer clinical history with multiple hemorrhages often makes total surgical resection difficult, partially because of the firmer capsule that may not shrink or collapse after hematoma is released. Pathologically those capsules were associated with more hyaline degeneration, fibrous proliferation and even calcifications. During the follow-up period between 0.5 to 11 years in 129 cases, 115 patients (89.2%) have been working, studying, or doing house work. Three patients (2.3%) suffered recurrent hemorrhages. Surgical indications of brain stem cavernoma include (1) progressive neurologic deficits; (2) overt acute or subacute hemorrhage on MRI either inside or outside cavernous malformations with mass effect; (3) cavernoma/hematoma reaching brainstem surface (<2 mm brain tissue between cavernoma /hematoma and pial surface). Grave clinical presentations like coma, respiratory, or cardiac instability are not surgical contraindications. Emergent surgical evacuation may lead to satisfactory outcome. Repeated hemorrhages will worsen the pre-existing neurologic deficits and possibly make the surgical dissections more difficult. Patients with minimum, stable neurologic deficits and lesion/hematoma that has not reached the brain stem surface should be followed conservatively.

The experimental study of genetic engineering human neural stem cells mediated by lentivirus to express multigene.

PubMed

Cai, Pei-qiang; Tang, Xun; Lin, Yue-qiu; Martin, Oudega; Sun, Guang-yun; Xu, Lin; Yang, Yun-kang; Zhou, Tian-hua

2006-02-01

To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully.

Self-organization of neural tissue architectures from pluripotent stem cells.

PubMed

Karus, Michael; Blaess, Sandra; Brüstle, Oliver

2014-08-15

Despite being a subject of intensive research, the mechanisms underlying the formation of neural tissue architectures during development of the central nervous system remain largely enigmatic. So far, studies into neural pattern formation have been restricted mainly to animal experiments. With the advent of pluripotent stem cells it has become possible to explore early steps of nervous system development in vitro. These studies have unraveled a remarkable propensity of primitive neural cells to self-organize into primitive patterns such as neural tube-like rosettes in vitro. Data from more advanced 3D culture systems indicate that this intrinsic propensity for self-organization can even extend to the formation of complex architectures such as a multilayered cortical neuroepithelium or an entire optic cup. These novel experimental paradigms not only demonstrate the enormous self-organization capacity of neural stem cells, they also provide exciting prospects for studying the earliest steps of human neural tissue development and the pathogenesis of brain malformations in reductionist in vitro paradigms. © 2014 Wiley Periodicals, Inc.

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

PubMed Central

Ying, Xue; Wang, Yahua; Xu, Haolun; Li, Xia; Yan, Helu; Tang, Hui; Wen, Chen; Li, Yingchun

2017-01-01

Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells. PMID:28969057

High-resolution anatomy of the human brain stem using 7-T MRI: improved detection of inner structures and nerves?

PubMed

Gizewski, Elke R; Maderwald, Stefan; Linn, Jennifer; Dassinger, Benjamin; Bochmann, Katja; Forsting, Michael; Ladd, Mark E

2014-03-01

The purpose of this paper is to assess the value of 7 Tesla (7 T) MRI for the depiction of brain stem and cranial nerve (CN) anatomy. Six volunteers were examined at 7 T using high-resolution SWI, MPRAGE, MP2RAGE, 3D SPACE T2, T2, and PD images to establish scanning parameters targeted at optimizing spatial resolution. Direct comparisons between 3 and 7 T were performed in two additional subjects using the finalized sequences (3 T: T2, PD, MPRAGE, SWAN; 7 T: 3D T2, MPRAGE, SWI, MP2RAGE). Artifacts and the depiction of structures were evaluated by two neuroradiologists using a standardized score sheet. Sequences could be established for high-resolution 7 T imaging even in caudal cranial areas. High in-plane resolution T2, PD, and SWI images provided depiction of inner brain stem structures such as pons fibers, raphe, reticular formation, nerve roots, and periaqueductal gray. MPRAGE and MP2RAGE provided clear depiction of the CNs. 3D T2 images improved depiction of inner brain structure in comparison to T2 images at 3 T. Although the 7-T SWI sequence provided improved contrast to some inner structures, extended areas were influenced by artifacts due to image disturbances from susceptibility differences. Seven-tesla imaging of basal brain areas is feasible and might have significant impact on detection and diagnosis in patients with specific diseases, e.g., trigeminal pain related to affection of the nerve root. Some inner brain stem structures can be depicted at 3 T, but certain sequences at 7 T, in particular 3D SPACE T2, are superior in producing anatomical in vivo images of deep brain stem structures.

Organotypic distribution of stem cell markers in formalin-fixed brain harboring glioblastoma multiforme.

PubMed

Schrot, Rudolph J; Ma, Joyce H; Greco, Claudia M; Arias, Angelo D; Angelastro, James M

2007-11-01

The role of stem cells in the origin, growth patterns, and infiltration of glioblastoma multiforme is a subject of intense investigation. One possibility is that glioblastoma may arise from transformed stem cells in the ventricular zone. To explore this hypothesis, we examined the distribution of two stem cell markers, activating transcription factor 5 (ATF5) and CD133, in an autopsy brain specimen from an individual with glioblastoma multiforme. A 41-year-old male with a right posterior temporal glioblastoma had undergone surgery, radiation, and chemotherapy. The brain was harvested within several hours after death. After formalin fixation, sectioning, and mapping of tumor location in the gross specimen, histologic specimens were prepared from tumor-bearing and grossly normal hemispheres. Fluorescence immunohistochemistry and colorimetric staining were performed for ATF5 and CD133. Both markers co-localized to the ependymal and subependymal zones on the side of the tumor, but not in the normal hemisphere or more rostrally in the affected hemisphere. ATF5 staining was especially robust within the diseased hemisphere in histologically normal ependyma. To our knowledge, this is the first in situ demonstration of stem cell markers in whole human brain. These preliminary results support the hypothesis that some glioblastomas may arise from the neurogenic zone of the lateral ventricle. The robust staining for ATF5 and CD133 in histologically normal ventricular zone suggests that an increase in periventricular stem cell activity occurred in this patient on the side of the tumor, either as a localized response to brain injury or as an integral component of oncogenesis and tumor recurrence.

Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity

PubMed Central

Komori, Hideyuki; Xiao, Qi; McCartney, Brooke M.; Lee, Cheng-Yu

2014-01-01

During asymmetric stem cell division, both the daughter stem cell and the presumptive intermediate progenitor cell inherit cytoplasm from their parental stem cell. Thus, proper specification of intermediate progenitor cell identity requires an efficient mechanism to rapidly extinguish the activity of self-renewal factors, but the mechanisms remain unknown in most stem cell lineages. During asymmetric division of a type II neural stem cell (neuroblast) in the Drosophila larval brain, the Brain tumor (Brat) protein segregates unequally into the immature intermediate neural progenitor (INP), where it specifies INP identity by attenuating the function of the self-renewal factor Klumpfuss (Klu), but the mechanisms are not understood. Here, we report that Brat specifies INP identity through its N-terminal B-boxes via a novel mechanism that is independent of asymmetric protein segregation. Brat-mediated specification of INP identity is critically dependent on the function of the Wnt destruction complex, which attenuates the activity of β-catenin/Armadillo (Arm) in immature INPs. Aberrantly increasing Arm activity in immature INPs further exacerbates the defects in the specification of INP identity and enhances the supernumerary neuroblast mutant phenotype in brat mutant brains. By contrast, reducing Arm activity in immature INPs suppresses supernumerary neuroblast formation in brat mutant brains. Finally, reducing Arm activity also strongly suppresses supernumerary neuroblasts induced by overexpression of klu. Thus, the Brat-dependent mechanism extinguishes the function of the self-renewal factor Klu in the presumptive intermediate progenitor cell by attenuating Arm activity, balancing stem cell maintenance and progenitor cell specification. PMID:24257623

Taking a Toll on Self-Renewal: TLR-Mediated Innate Immune Signaling in Stem Cells.

PubMed

Alvarado, Alvaro G; Lathia, Justin D

2016-07-01

Innate immunity has evolved as the front-line cellular defense mechanism to acutely sense and decisively respond to microenvironmental alterations. The Toll-like receptor (TLR) family activates signaling pathways in response to stimuli and is well-characterized in both resident and infiltrating immune cells during neural inflammation, injury, and degeneration. Innate immune signaling has also been observed in neural cells during development and disease, including in the stem and progenitor cells that build the brain and are responsible for its homeostasis. Recently, the activation of developmental programs in malignant brain tumors has emerged as a driver for growth via cancer stem cells. In this review we discuss how innate immune signaling interfaces with stem cell maintenance in the normal and neoplastic brain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

ClinicalTrials.gov

2013-10-07

Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Functional recovery after injury of motor cortex in rats: effects of rehabilitation and stem cell transplantation in a traumatic brain injury model of cortical resection.

PubMed

Lee, Do-Hun; Lee, Ji Yeoun; Oh, Byung-Mo; Phi, Ji Hoon; Kim, Seung-Ki; Bang, Moon Suk; Kim, Seung U; Wang, Kyu-Chang

2013-03-01

Experimental studies and clinical trials designed to help patients recover from various brain injuries, such as stroke or trauma, have been attempted. Rehabilitation has shown reliable, positive clinical outcome in patients with various brain injuries. Transplantation of exogenous neural stem cells (NSCs) to repair the injured brain is a potential tool to help patient recovery. This study aimed to evaluate the therapeutic efficacy of a combination therapy consisting of rehabilitation and NSC transplantation compared to using only one modality. A model of motor cortex resection in rats was used to create brain injury in order to obtain consistent and prolonged functional deficits. The therapeutic results were evaluated using three methods during an 8-week period with a behavioral test, motor-evoked potential (MEP) measurement, and measurement of the degree of endogenous NSC production. All three treatment groups showed the effects of treatment in the behavioral test, although the NSC transplantation alone group (CN) exhibited slightly worse results than the rehabilitation alone group (CR) or the combination therapy group (CNR). The latency on MEP was shortened to a similar extent in all three groups compared to the untreated group (CO). However, the enhancement of endogenous NSC proliferation was dramatically reduced in the CN group compared not only to the CR and CNR groups but also to the CO group. The CR and CNR groups seemed to prolong the duration of endogenous NSC proliferation compared to the untreated group. A combination of rehabilitation and NSC transplantation appears to induce treatment outcomes that are similar to rehabilitation alone. Further studies are needed to evaluate the electrophysiological outcome of recovery and the possible effect of prolonging endogenous NSC proliferation in response to NSC transplantation and rehabilitation.

Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer.

PubMed

McGowan, Patricia M; Simedrea, Carmen; Ribot, Emeline J; Foster, Paula J; Palmieri, Diane; Steeg, Patricia S; Allan, Alison L; Chambers, Ann F

2011-07-01

Brain metastasis from breast cancer is an increasingly important clinical problem. Here we assessed the role of CD44(hi)/CD24(lo) cells and pathways that regulate them, in an experimental model of brain metastasis. Notch signaling (mediated by γ-secretase) has been shown to contribute to maintenance of the cancer stem cell (CSC) phenotype. Cells sorted for a reduced stem-like phenotype had a reduced ability to form brain metastases compared with unsorted or CD44(hi)/CD24(lo) cells (P < 0.05; Kruskal-Wallis). To assess the effect of γ-secretase inhibition, cells were cultured with DAPT and the CD44/CD24 phenotypes quantified. 231-BR cells with a CD44(hi)/CD24(lo) phenotype was reduced by about 15% in cells treated with DAPT compared with DMSO-treated or untreated cells (P = 0.001, ANOVA). In vivo, mice treated with DAPT developed significantly fewer micro- and macrometastases compared with vehicle treated or untreated mice (P = 0.011, Kruskal-Wallis). Notch1 knockdown reduced the expression of CD44(hi)/CD24(lo) phenotype by about 20%. In vitro, Notch1 shRNA resulted in a reduction in cellular growth at 24, 48, and 72 hours time points (P = 0.033, P = 0.002, and P = 0.009, ANOVA) and about 60% reduction in Matrigel invasion was observed (P < 0.001, ANOVA). Cells transfected with shNotch1 formed significantly fewer macrometastases and micrometastases compared with scrambled shRNA or untransfected cells (P < 0.001; Kruskal-Wallis). These data suggest that the CSC phenotype contributes to the development of brain metastases from breast cancer, and this may arise in part from increased Notch activity. ©2011 AACR.

Electrophysiological properties of neurons derived from human stem cells and iNeurons in vitro.

PubMed

Halliwell, Robert F

2017-06-01

Functional studies of neurons have traditionally used nervous system tissues from a variety of non-human vertebrate and invertebrate species, even when the focus of much of this research has been directed at understanding human brain function. Over the last decade, the identification and isolation of human stem cells from embryonic, tissue (or adult) and induced pluripotent stem cells (iPSCs) has revolutionized the availability of human neurons for experimental studies in vitro. In addition, the direct conversion of terminally differentiated fibroblasts into Induced neurons (iN) has generated great excitement because of the likely value of such human stem cell derived neurons (hSCNs) and iN cells in drug discovery, neuropharmacology, neurotoxicology and regenerative medicine. This review addresses the current state of our knowledge of functional receptors and ion channels expressed in neurons derived from human stem cells and iNeurons and identifies gaps and questions that might be investigated in future studies; it focusses almost exclusively on what is known about the electrophysiological properties of neurons derived from human stem cells and iN cells in vitro with an emphasis on voltage and ligand gated ion channels, since these mediate synaptic signalling in the nervous system and they are at the heart of neuropharmacology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain components

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The brain is composed of more than a thousand billion neurons. Specific groups of them, working in concert, provide ... of information. The 3 major components of the brain are the cerebrum, cerebellum, and brain stem. The ...

Brain tumour stem cells: implications for cancer therapy and regenerative medicine.

PubMed

Sanchez-Martin, Manuel

2008-09-01

The cancer relapse and mortality rate suggest that current therapies do not eradicate all malignant cells. Currently, it is accepted that tumorigenesis and organogenesis are similar in many respects, as for example, homeostasis is governed by a distinct sub-population of stem cells in both situations. There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells (CSC), which are characterized by their self-renewing capacity and differentiation ability. The investigation of solid tumour stem cells has gained momentum particularly in the area of brain tumours. Gliomas are the most common type of primary brain tumours. Nearly two-thirds of gliomas are highly malignant lesions with fast progression and unfortunate prognosis. Despite recent advances, two-year survival for glioblastoma (GBM) with optimal therapy is less than 30%. Even among patients with low-grade gliomas that confer a relatively good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and a tumour-initiating function. In general, this fraction is characterized for forming neurospheres, being endowed with drug resistance properties and often, we can isolate some of them using sorting methods with specific antibodies. The molecular characterization of these stem populations will be critical to developing an effective therapy for these tumours with very dismal prognosis. To achieve this aim, the development of a mouse model which recapitulates the nature of these tumours is essential. This review will focus on glioma stem cell knowledge and discuss future implications in brain cancer therapy and regenerative medicine.

Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, "protective" glial stem cells and stromal ependymal cells.

PubMed

Hauwel, Mathieu; Furon, Emeline; Canova, Cecile; Griffiths, Mark; Neal, Jim; Gasque, Philippe

2005-04-01

In invertebrates and primitive vertebrates, the brain contains large numbers of "professional" macrophages associated with neurones, ependymal tanycytes and radial glia to promote robust regenerative capacity. In higher vertebrates, hematogenous cells are largely excluded from the brain, and innate immune molecules and receptors produced by the resident "amateur" macrophages (microglia, astrocytes and ependymal cells) control pathogen infiltration and clearance of toxic cell debris. However, there is minimal capacity for regeneration. The transfer of function from hematogenous cells to macroglia and microglia is associated with the sophistication of a yet poorly-characterized neurone-glia network. This evolutionary pattern may have been necessary to reduce the risk of autoimmune attack while preserving the neuronal web but the ability to repair central nervous system damage may have been sacrificed in the process. We herein argue that it may be possible to re-educate and stimulate the resident phagocytes to promote clearance of pathogens (e.g., Prion), toxic cell debris (e.g., amyloid fibrils and myelin) and apoptotic cells. Moreover, as part of this greater division of labour between cell types in vertebrate brains, it may be possible to harness the newly described properties of glial stem cells in neuronal protection (revitalization) rather than replacement, and to control brain inflammation. We will also highlight the emerging roles of stromal ependymal cells in controlling stem cell production and migration into areas of brain damage. Understanding the mechanisms involved in the nurturing of damaged neurons by protective glial stem cells with the safe clearance of cell debris could lead to remedial strategies for chronic brain diseases.

DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates.

PubMed

Keeney, J G; Davis, J M; Siegenthaler, J; Post, M D; Nielsen, B S; Hopkins, W D; Sikela, J M

2015-09-01

Genome sequences encoding DUF1220 protein domains show a burst in copy number among anthropoid species and especially humans, where they have undergone the greatest human lineage-specific copy number expansion of any protein coding sequence in the genome. While DUF1220 copy number shows a dosage-related association with brain size in both normal populations and in 1q21.1-associated microcephaly and macrocephaly, a function for these domains has not yet been described. Here we provide multiple lines of evidence supporting the view that DUF1220 domains function as drivers of neural stem cell proliferation among anthropoid species including humans. First, we show that brain MRI data from 131 individuals across 7 anthropoid species shows a strong correlation between DUF1220 copy number and multiple brain size-related measures. Using in situ hybridization analyses of human fetal brain, we also show that DUF1220 domains are expressed in the ventricular zone and primarily during human cortical neurogenesis, and are therefore expressed at the right time and place to be affecting cortical brain development. Finally, we demonstrate that in vitro expression of DUF1220 sequences in neural stem cells strongly promotes proliferation. Taken together, these data provide the strongest evidence so far reported implicating DUF1220 dosage in anthropoid and human brain expansion through mechanisms involving increasing neural stem cell proliferation.

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke.

PubMed

Wei, Ling; Wei, Zheng Z; Jiang, Michael Qize; Mohamad, Osama; Yu, Shan Ping

2017-10-01

One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke. Copyright © 2017 Elsevier Ltd. All rights reserved.

The "pseudo-CT myelogram sign": an aid to the diagnosis of underlying brain stem and spinal cord trauma in the presence of major craniocervical region injury on post-mortem CT.

PubMed

Bolster, F; Ali, Z; Daly, B

2017-12-01

To document the detection of underlying low-attenuation spinal cord or brain stem injuries in the presence of the "pseudo-CT myelogram sign" (PCMS) on post-mortem computed tomography (PMCT). The PCMS was identified on PMCT in 20 decedents (11 male, nine female; age 3-83 years, mean age 35.3 years) following fatal blunt trauma at a single forensic centre. Osseous and ligamentous craniocervical region injuries and brain stem or spinal cord trauma detectable on PMCT were recorded. PMCT findings were compared to conventional autopsy in all cases. PMCT-detected transection of the brain stem or high cervical cord in nine of 10 cases compared to autopsy (90% sensitivity). PMCT was 92.86% sensitive in detection of atlanto-occipital joint injuries (n=14), and 100% sensitive for atlanto-axial joint (n=8) injuries. PMCT detected more cervical spine and skull base fractures (n=22, and n=10, respectively) compared to autopsy (n=13, and n=5, respectively). The PCMS is a novel description of a diagnostic finding, which if present in fatal craniocervical region trauma, is very sensitive for underlying spinal cord and brain stem injuries not ordinarily visible on PMCT. Its presence may also predict major osseous and/or ligamentous injuries in this region when anatomical displacement is not evident on PMCT. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Effects of atelocollagen on neural stem cell function and its migrating capacity into brain in psychiatric disease model.

PubMed

Yoshinaga, Toshihiro; Hashimoto, Eri; Ukai, Wataru; Ishii, Takao; Shirasaka, Tomohiro; Kigawa, Yoshiyasu; Tateno, Masaru; Kaneta, Hiroo; Watanabe, Kimihiko; Igarashi, Takeshi; Kobayashi, Seiju; Sohma, Hitoshi; Kato, Tadafumi; Saito, Toshikazu

2013-10-01

Stem cell therapy is well proposed as a potential method for the improvement of neurodegenerative damage in the brain. Among several different procedures to reach the cells into the injured lesion, the intravenous (IV) injection has benefit as a minimally invasive approach. However, for the brain disease, prompt development of the effective treatment way of cellular biodistribution of stem cells into the brain after IV injection is needed. Atelocollagen has been used as an adjunctive material in a gene, drug and cell delivery system because of its extremely low antigenicity and bioabsorbability to protect these transplants from intrabody environment. However, there is little work about the direct effect of atelocollagen on stem cells, we examined the functional change of survival, proliferation, migration and differentiation of cultured neural stem cells (NSCs) induced by atelocollagen in vitro. By 72-h treatment 0.01-0.05% atelocollagen showed no significant effects on survival, proliferation and migration of NSCs, while 0.03-0.05% atelocollagen induced significant reduction of neuronal differentiation and increase of astrocytic differentiation. Furthermore, IV treated NSCs complexed with atelocollagen (0.02%) could effectively migrate into the brain rather than NSC treated alone using chronic alcohol binge model rat. These experiments suggested that high dose of atelocollagen exerts direct influence on NSC function but under 0.03% of atelocollagen induces beneficial effect on regenerative approach of IV administration of NSCs for CNS disease.

Brain injury expands the numbers of neural stem cells and progenitors in the SVZ by enhancing their responsiveness to EGF

PubMed Central

Alagappan, Dhivyaa; Lazzarino, Deborah A; Felling, Ryan J; Balan, Murugabaskar; Kotenko, Sergei V; Levison, Steven W

2009-01-01

There is an increase in the numbers of neural precursors in the SVZ (subventricular zone) after moderate ischaemic injuries, but the extent of stem cell expansion and the resultant cell regeneration is modest. Therefore our studies have focused on understanding the signals that regulate these processes towards achieving a more robust amplification of the stem/progenitor cell pool. The goal of the present study was to evaluate the role of the EGFR [EGF (epidermal growth factor) receptor] in the regenerative response of the neonatal SVZ to hypoxic/ischaemic injury. We show that injury recruits quiescent cells in the SVZ to proliferate, that they divide more rapidly and that there is increased EGFR expression on both putative stem cells and progenitors. With the amplification of the precursors in the SVZ after injury there is enhanced sensitivity to EGF, but not to FGF (fibroblast growth factor)-2. EGF-dependent SVZ precursor expansion, as measured using the neurosphere assay, is lost when the EGFR is pharmacologically inhibited, and forced expression of a constitutively active EGFR is sufficient to recapitulate the exaggerated proliferation of the neural stem/progenitors that is induced by hypoxic/ischaemic brain injury. Cumulatively, our results reveal that increased EGFR signalling precedes that increase in the abundance of the putative neural stem cells and our studies implicate the EGFR as a key regulator of the expansion of SVZ precursors in response to brain injury. Thus modulating EGFR signalling represents a potential target for therapies to enhance brain repair from endogenous neural precursors following hypoxic/ischaemic and other brain injuries. PMID:19570028

Effects of irradiation on stem cell response to differentiation inhibitors in the Planarian Dugesia etrusca

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steele, V.E.; Lange, C.S.

1976-07-01

The planarian owes its extensive powers of regeneration to the possession of a totipotential stem cell system. The survival of the animal after irradiation depends mainly upon this system. In this respect the planarian is analogous to mammalian organ systems such as bone marrow or gut epithelium. The differentiated cells control the course of stem cell mediated tissue renewal by the secretion of differentiator and/or inhibitor substances. One such inhibitor substance, present in extracts prepared from homogenized whole planarians, specifically inhibits brain formation. This substance is organ specific, but not species specific. The differentiative integrity of the stem cells aftermore » irradiation is measured by comparing the regenerated brain volumes resulting from the presence or absence of the brain inhibitory extract during the regeneration period. Our data suggest that increasing doses of x irradiation decreases the ability of the stem cells to respond to differentiative substances. The data presented also explore the possibility of altering the postirradiation recovery pattern by shifting the differentiative demands placed on the stem cells. The final proportions of animals (one-half regenerated with, and one-half without, the extract) surviving after 60 days were not significantly different.« less

Segmentation and texture analysis of structural biomarkers using neighborhood-clustering-based level set in MRI of the schizophrenic brain.

PubMed

Latha, Manohar; Kavitha, Ganesan

2018-02-03

Schizophrenia (SZ) is a psychiatric disorder that especially affects individuals during their adolescence. There is a need to study the subanatomical regions of SZ brain on magnetic resonance images (MRI) based on morphometry. In this work, an attempt was made to analyze alterations in structure and texture patterns in images of the SZ brain using the level-set method and Laws texture features. T1-weighted MRI of the brain from Center of Biomedical Research Excellence (COBRE) database were considered for analysis. Segmentation was carried out using the level-set method. Geometrical and Laws texture features were extracted from the segmented brain stem, corpus callosum, cerebellum, and ventricle regions to analyze pattern changes in SZ. The level-set method segmented multiple brain regions, with higher similarity and correlation values compared with an optimized method. The geometric features obtained from regions of the corpus callosum and ventricle showed significant variation (p < 0.00001) between normal and SZ brain. Laws texture feature identified a heterogeneous appearance in the brain stem, corpus callosum and ventricular regions, and features from the brain stem were correlated with Positive and Negative Syndrome Scale (PANSS) score (p < 0.005). A framework of geometric and Laws texture features obtained from brain subregions can be used as a supplement for diagnosis of psychiatric disorders.

Recovery from a possible cytomegalovirus meningoencephalitis-induced apparent brain stem death in an immunocompetent man: a case report.

PubMed

Rahardjo, Theresia Monica; Maskoen, Tinni Trihartini; Redjeki, Ike Sri

2016-08-26

Recovery from cytomegalovirus meningoencephalitis with brain stem death in an immunocompetent patient is almost impossible. We present a remarkable recovery from a possible cytomegalovirus infection in an immunocompetent man who had severe neurological syndromes, suggesting brain stem death complicated by pneumonia and pleural effusion. A 19-year-old Asian man presented at our hospital's emergency department with reduced consciousness and seizures following high fever, headache, confusion, and vomitus within a week before arrival. He was intubated and sent to our intensive care unit. He had nuchal rigidity and tetraparesis with accentuated tendon reflexes. Electroencephalography findings suggested an acute structural lesion at his right temporal area or an epileptic state. A cerebral spinal fluid examination suggested viral infection. A computed tomography scan was normal at the early stage of disease. Immunoglobulin M, immunoglobulin G anti-herpes simplex virus, and immunoglobulin M anti-cytomegalovirus were negative. However, immunoglobulin G anti-cytomegalovirus was positive, which supported a diagnosis of cytomegalovirus meningoencephalitis. His clinical condition deteriorated, spontaneous respiration disappeared, cranial reflexes became negative, and brain stem death was suspected. Therapy included antivirals, corticosteroids, antibiotics, anticonvulsant, antipyretics, antifungal agents, and a vasopressor to maintain hemodynamic stability. After 1 month, he showed a vague response to painful stimuli at his supraorbital nerve and respiration started to appear the following week. After pneumonia and pleural effusion were resolved, he was weaned from the ventilator and moved from the intensive care unit on day 90. This case highlights several important issues that should be considered. First, the diagnosis of brain stem death must be confirmed with caution even if there are negative results of brain stem death test for a long period. Second, cytomegalovirus meningoencephalitis should be considered in the differential diagnosis even for an immunocompetent adult. Third, accurate therapy and simultaneous intensive care have very important roles in the recovery process of patients with cytomegalovirus meningoencephalitis.

Intermittent hypoxia activates peptidylglycine α-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing

PubMed Central

Sharma, Suresh D.; Raghuraman, Gayatri; Lee, Myeong-Seon; Prabhakar, Nanduri R.; Kumar, Ganesh K.

2009-01-01

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine α-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the α-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O2-sensitive peptidylglycine α-hydroxylating monooxygenase (PHM) and peptidyl-α-hydroxyglycine α-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O2 for 15 s followed by 21% O2 for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of α-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM (∼1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases Vmax but has no effect on Km. IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem. PMID:18818385

Intermittent hypoxia activates peptidylglycine alpha-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing.

PubMed

Sharma, Suresh D; Raghuraman, Gayatri; Lee, Myeong-Seon; Prabhakar, Nanduri R; Kumar, Ganesh K

2009-01-01

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the alpha-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O(2)-sensitive peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O(2) for 15 s followed by 21% O(2) for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of alpha-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM ( approximately 1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases V(max) but has no effect on K(m). IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

PubMed

Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-06

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer.

Orphan nuclear receptor TLX activates Wnt/β-catenin signalling to stimulate neural stem cell proliferation and self-renewal

PubMed Central

Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.; Shi, Yanhong

2010-01-01

The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/β-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/β-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active β-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a β-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active β-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active β-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active β-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/β-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode. PMID:20010817

Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal.

PubMed

Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T; Gage, Fred H; Evans, Ronald M; Shi, Yanhong

2010-01-01

The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/beta-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/beta-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active beta-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a beta-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active beta-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active beta-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active beta-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/beta-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode.

Quantitative Assessment of Normal Fetal Brain Myelination Using Fast Macromolecular Proton Fraction Mapping.

PubMed

Yarnykh, V L; Prihod'ko, I Y; Savelov, A A; Korostyshevskaya, A M

2018-05-10

Fast macromolecular proton fraction mapping is a recently emerged MRI method for quantitative myelin imaging. Our aim was to develop a clinically targeted technique for macromolecular proton fraction mapping of the fetal brain and test its capability to characterize normal prenatal myelination. This prospective study included 41 pregnant women (gestational age range, 18-38 weeks) without abnormal findings on fetal brain MR imaging performed for clinical indications. A fast fetal brain macromolecular proton fraction mapping protocol was implemented on a clinical 1.5T MR imaging scanner without software modifications and was performed after a clinical examination with an additional scan time of <5 minutes. 3D macromolecular proton fraction maps were reconstructed from magnetization transfer-weighted, T1-weighted, and proton density-weighted images by the single-point method. Mean macromolecular proton fraction in the brain stem, cerebellum, and thalamus and frontal, temporal, and occipital WM was compared between structures and pregnancy trimesters using analysis of variance. Gestational age dependence of the macromolecular proton fraction was assessed using the Pearson correlation coefficient ( r ). The mean macromolecular proton fraction in the fetal brain structures varied between 2.3% and 4.3%, being 5-fold lower than macromolecular proton fraction in adult WM. The macromolecular proton fraction in the third trimester was higher compared with the second trimester in the brain stem, cerebellum, and thalamus. The highest macromolecular proton fraction was observed in the brain stem, followed by the thalamus, cerebellum, and cerebral WM. The macromolecular proton fraction in the brain stem, cerebellum, and thalamus strongly correlated with gestational age ( r = 0.88, 0.80, and 0.73; P < .001). No significant correlations were found for cerebral WM regions. Myelin is the main factor determining macromolecular proton fraction in brain tissues. Macromolecular proton fraction mapping is sensitive to the earliest stages of the fetal brain myelination and can be implemented in a clinical setting. © 2018 by American Journal of Neuroradiology.

Release of endogenous amino acids from the hippocampus and brain stem from developing and adult mice in ischemia.

PubMed

Oja, Simo S; Saransaari, Pirjo

2009-09-01

The release of neurotransmitters and modulators has been studied mostly using labeled preloaded compounds. For several reasons, however, the estimated release may not reliably reflect the release of endogenous compounds. The basal and K(+)-evoked release of the neuroactive endogenous amino acids GABA, glycine, taurine, L-glutamate and L-aspartate was now studied in slices from the hippocampus and brain stem from 7-day-old and 3-month-old mice under control and ischemic conditions. The release of synaptically not active L-glutamine, L-alanine, L-threonine and L-serine was assessed for comparison. The estimates for the hippocampus and brainstem were markedly different and also different in developing and adult mice. GABA release was much greater in 3-month-old than in 7-day-old mice, whereas with taurine the situation was the opposite, in the hippocampus in particular. K(+) stimulation enhanced glycine release more in the mature than immature brain stem while in the hippocampus the converse was observed. Ischemia enhanced the release of all neuroactive amino acids in both brain regions, the effects being relatively most pronounced in the case of GABA, aspartate and glutamate in the hippocampus in 3-month-old mice, and taurine in 7-day-old and glycine in 3-month-old mice in the brain stem. These results are qualitatively similar to those obtained on earlier experiments with labeled preloaded amino acids. However, the magnitudes of the release cannot be quite correctly estimated using radioactive labels. In developing mice only taurine release may counteract the harmful effects of excitatory amino acids in ischemia in both hippocampus and brain stem.

Stem Cell Technology for (Epi)genetic Brain Disorders.

PubMed

Riemens, Renzo J M; Soares, Edilene S; Esteller, Manel; Delgado-Morales, Raul

2017-01-01

Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).

Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms.

PubMed

Gleitz, Hélène Fe; Liao, Ai Yin; Cook, James R; Rowlston, Samuel F; Forte, Gabriella Ma; D'Souza, Zelpha; O'Leary, Claire; Holley, Rebecca J; Bigger, Brian W

2018-06-08

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross-correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE-dependent receptors and mannose-6-phosphate receptors. Brain-targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Rhythm generation, coordination, and initiation in the vocal pathways of male African clawed frogs

PubMed Central

Cavin Barnes, Jessica; Appleby, Todd

2016-01-01

Central pattern generators (CPGs) in the brain stem are considered to underlie vocalizations in many vertebrate species, but the detailed mechanisms underlying how motor rhythms are generated, coordinated, and initiated remain unclear. We addressed these issues using isolated brain preparations of Xenopus laevis from which fictive vocalizations can be elicited. Advertisement calls of male X. laevis that consist of fast and slow trills are generated by vocal CPGs contained in the brain stem. Brain stem central vocal pathways consist of a premotor nucleus [dorsal tegmental area of medulla (DTAM)] and a laryngeal motor nucleus [a homologue of nucleus ambiguus (n.IX-X)] with extensive reciprocal connections between the nuclei. In addition, DTAM receives descending inputs from the extended amygdala. We found that unilateral transection of the projections between DTAM and n.IX-X eliminated premotor fictive fast trill patterns but did not affect fictive slow trills, suggesting that the fast and slow trill CPGs are distinct; the slow trill CPG is contained in n.IX-X, and the fast trill CPG spans DTAM and n.IX-X. Midline transections that eliminated the anterior, posterior, or both commissures caused no change in the temporal structure of fictive calls, but bilateral synchrony was lost, indicating that the vocal CPGs are contained in the lateral halves of the brain stem and that the commissures synchronize the two oscillators. Furthermore, the elimination of the inputs from extended amygdala to DTAM, in addition to the anterior commissure, resulted in autonomous initiation of fictive fast but not slow trills by each hemibrain stem, indicating that the extended amygdala provides a bilateral signal to initiate fast trills. NEW & NOTEWORTHY Central pattern generators (CPGs) are considered to underlie vocalizations in many vertebrate species, but the detailed mechanisms underlying their functions remain unclear. We addressed this question using an isolated brain preparation of African clawed frogs. We discovered that two vocal phases are mediated by anatomically distinct CPGs, that there are a pair of CPGs contained in the left and right half of the brain stem, and that mechanisms underlying initiation of the two vocal phases are distinct. PMID:27760822

Brain stem death and organ donation.

PubMed

Davies, C

1996-01-01

Our understanding of the concept and definition of death has changed over time. The British contribution to the body of knowledge on the diagnosis of brain steam death was the publication by the medical royal colleges (1976) of diagnostic criteria. Most literature and research which explores the knowledge and attitudes of nurses towards the concept of brain stem death is from the USA. Several issues which arise from the literature are discussed in relation to organ donation. Further UK-based research is required.

Robotics, stem cells, and brain-computer interfaces in rehabilitation and recovery from stroke: updates and advances.

PubMed

Boninger, Michael L; Wechsler, Lawrence R; Stein, Joel

2014-11-01

The aim of this study was to describe the current state and latest advances in robotics, stem cells, and brain-computer interfaces in rehabilitation and recovery for stroke. The authors of this summary recently reviewed this work as part of a national presentation. The article represents the information included in each area. Each area has seen great advances and challenges as products move to market and experiments are ongoing. Robotics, stem cells, and brain-computer interfaces all have tremendous potential to reduce disability and lead to better outcomes for patients with stroke. Continued research and investment will be needed as the field moves forward. With this investment, the potential for recovery of function is likely substantial.

The direct connections of the C2 dorsal ganglion in the brain stem of the squirrel monkey: a preliminary investigation *

PubMed Central

Fitz-Ritson, Don E.

1979-01-01

The purpose of this investigation was to observe the possible anatomical connections of C2 dorsal root with brain stem nuclei. Labelled amino acids (leucine, glycine, proline), were injected into the dorsal root of C2 of a squirrel monkey. The animal was allowed to survive for 20 hrs. and after, sections of the spinal cord and brain stem were subjected to autoradiographic methods. Direct connections were observed in Lamina II, VII, VIII of the spinal cord; the hypoglossal nucleus, medial vestibular nucleus, lateral cuneatus nucleus and lateral parvocellular reticular formation. Possible anatomical and physiological correlates are explored in relation to the importance of the upper cervical area and its control mechanisms.

Robotics, Stem Cells and Brain Computer Interfaces in Rehabilitation and Recovery from Stroke; Updates and Advances

PubMed Central

Boninger, Michael L; Wechsler, Lawrence R.; Stein, Joel

2014-01-01

Objective To describe the current state and latest advances in robotics, stem cells, and brain computer interfaces in rehabilitation and recovery for stroke. Design The authors of this summary recently reviewed this work as part of a national presentation. The paper represents the information included in each area. Results Each area has seen great advances and challenges as products move to market and experiments are ongoing. Conclusion Robotics, stem cells, and brain computer interfaces all have tremendous potential to reduce disability and lead to better outcomes for patients with stroke. Continued research and investment will be needed as the field moves forward. With this investment, the potential for recovery of function is likely substantial PMID:25313662

Meta-Analysis and Experimental Validation Identified FREM2 and SPRY1 as New Glioblastoma Marker Candidates.

PubMed

Vidak, Marko; Jovcevska, Ivana; Samec, Neja; Zottel, Alja; Liovic, Mirjana; Rozman, Damjana; Dzeroski, Saso; Juvan, Peter; Komel, Radovan

2018-05-04

Glioblastoma (GB) is the most aggressive brain malignancy. Although some potential glioblastoma biomarkers have already been identified, there is a lack of cell membrane-bound biomarkers capable of distinguishing brain tissue from glioblastoma and/or glioblastoma stem cells (GSC), which are responsible for the rapid post-operative tumor reoccurrence. In order to find new GB/GSC marker candidates that would be cell surface proteins (CSP), we have performed meta-analysis of genome-scale mRNA expression data from three data repositories (GEO, ArrayExpress and GLIOMASdb). The search yielded ten appropriate datasets, and three (GSE4290/GDS1962, GSE23806/GDS3885, and GLIOMASdb) were used for selection of new GB/GSC marker candidates, while the other seven (GSE4412/GDS1975, GSE4412/GDS1976, E-GEOD-52009, E-GEOD-68848, E-GEOD-16011, E-GEOD-4536, and E-GEOD-74571) were used for bioinformatic validation. The selection identified four new CSP-encoding candidate genes— CD276 , FREM2 , SPRY1 , and SLC47A1 —and the bioinformatic validation confirmed these findings. A review of the literature revealed that CD276 is not a novel candidate, while SLC47A1 had lower validation test scores than the other new candidates and was therefore not considered for experimental validation. This validation revealed that the expression of FREM2—but not SPRY1—is higher in glioblastoma cell lines when compared to non-malignant astrocytes. In addition, FREM2 gene and protein expression levels are higher in GB stem-like cell lines than in conventional glioblastoma cell lines. FREM2 is thus proposed as a novel GB biomarker and a putative biomarker of glioblastoma stem cells. Both FREM2 and SPRY1 are expressed on the surface of the GB cells, while SPRY1 alone was found overexpressed in the cytosol of non-malignant astrocytes.

Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.

PubMed

Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal

2017-03-01

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats

PubMed Central

2012-01-01

Background Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload. Methods Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl3), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d. Results Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls. Conclusion Aluminum overload increases oxidative stress (H2O2) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats. PMID:22613782

Regional volumes in brain stem and cerebellum are associated with postural impairments in young brain-injured patients.

PubMed

Drijkoningen, David; Leunissen, Inge; Caeyenberghs, Karen; Hoogkamer, Wouter; Sunaert, Stefan; Duysens, Jacques; Swinnen, Stephan P

2015-12-01

Many patients with traumatic brain injury (TBI) suffer from postural control impairments that can profoundly affect daily life. The cerebellum and brain stem are crucial for the neural control of posture and have been shown to be vulnerable to primary and secondary structural consequences of TBI. The aim of this study was to investigate whether morphometric differences in the brain stem and cerebellum can account for impairments in static and dynamic postural control in TBI. TBI patients (n = 18) and healthy controls (n = 30) completed three challenging postural control tasks on the EquiTest® system (Neurocom). Infratentorial grey matter (GM) and white matter (WM) volumes were analyzed with cerebellum-optimized voxel-based morphometry using the spatially unbiased infratentorial toolbox. Volume loss in TBI patients was revealed in global cerebellar GM, global infratentorial WM, middle cerebellar peduncles, pons and midbrain. In the TBI group and across both groups, lower postural control performance was associated with reduced GM volume in the vermal/paravermal regions of lobules I-IV, V and VI. Moreover, across all participants, worse postural control performance was associated with lower WM volume in the pons, medulla, midbrain, superior and middle cerebellar peduncles and cerebellum. This is the first study in TBI patients to demonstrate an association between postural impairments and reduced volume in specific infratentorial brain areas. Volumetric measures of the brain stem and cerebellum may be valuable prognostic markers of the chronic neural pathology, which complicates rehabilitation of postural control in TBI. © 2015 Wiley Periodicals, Inc.

Neural stem cells encapsulated in a functionalized self-assembling peptide hydrogel for brain tissue engineering.

PubMed

Cheng, Tzu-Yun; Chen, Ming-Hong; Chang, Wen-Han; Huang, Ming-Yuan; Wang, Tzu-Wei

2013-03-01

Brain injury is almost irreparable due to the poor regenerative capability of neural tissue. Nowadays, new therapeutic strategies have been focused on stem cell therapy and supplying an appropriate three dimensional (3D) matrix for the repair of injured brain tissue. In this study, we specifically linked laminin-derived IKVAV motif on the C-terminal to enrich self-assembling peptide RADA(16) as a functional peptide-based scaffold. Our purpose is providing a functional self-assembling peptide 3D hydrogel with encapsulated neural stem cells to enhance the reconstruction of the injured brain. The physiochemical properties reported that RADA(16)-IKVAV can self-assemble into nanofibrous morphology with bilayer β-sheet structure and become gelationed hydrogel with mechanical stiffness similar to brain tissue. The in vitro results showed that the extended IKVAV sequence can serve as a signal or guiding cue to direct the encapsulated neural stem cells (NSCs) adhesion and then towards neuronal differentiation. Animal study was conducted in a rat brain surgery model to demonstrate the damage in cerebral neocortex/neopallium loss. The results showed that the injected peptide solution immediately in situ formed the 3D hydrogel filling up the cavity and bridging the gaps. The histological analyses revealed the RADA(16)-IKVAV self-assembling peptide hydrogel not only enhanced survival of encapsulated NSCs but also reduced the formation of glial astrocytes. The peptide hydrogel with IKVAV extended motifs also showed the support of encapsulated NSCs in neuronal differentiation and the improvement in brain tissue regeneration after 6 weeks post-transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Store-Operated Calcium Entries Control Neural Stem Cell Self-Renewal in the Adult Brain Subventricular Zone.

PubMed

Domenichini, Florence; Terrié, Elodie; Arnault, Patricia; Harnois, Thomas; Magaud, Christophe; Bois, Patrick; Constantin, Bruno; Coronas, Valérie

2018-05-01

The subventricular zone (SVZ) is the major stem cell niche in the brain of adult mammals. Within this region, neural stem cells (NSC) proliferate, self-renew and give birth to neurons and glial cells. Previous studies underlined enrichment in calcium signaling-related transcripts in adult NSC. Because of their ability to mobilize sustained calcium influxes in response to a wide range of extracellular factors, store-operated channels (SOC) appear to be, among calcium channels, relevant candidates to induce calcium signaling in NSC whose cellular activities are continuously adapted to physiological signals from the microenvironment. By Reverse Transcription Polymerase Chain Reaction (RT-PCR), Western blotting and immunocytochemistry experiments, we demonstrate that SVZ cells express molecular actors known to build up SOC, namely transient receptor potential canonical 1 (TRPC1) and Orai1, as well as their activator stromal interaction molecule 1 (STIM1). Calcium imaging reveals that SVZ cells display store-operated calcium entries. Pharmacological blockade of SOC with SKF-96365 or YM-58483 (also called BTP2) decreases proliferation, impairs self-renewal by shifting the type of SVZ stem cell division from symmetric proliferative to asymmetric, thereby reducing the stem cell population. Brain section immunostainings show that TRPC1, Orai1, and STIM1 are expressed in vivo, in SOX2-positive SVZ NSC. Injection of SKF-96365 in brain lateral ventricle diminishes SVZ cell proliferation and reduces the ability of SVZ cells to form neurospheres in vitro. The present study combining in vitro and in vivo approaches uncovers a major role for SOC in the control of SVZ NSC population and opens new fields of investigation for stem cell biology in health and disease. Stem Cells 2018;36:761-774. © AlphaMed Press 2018.

Regulation of endogenous neural stem/progenitor cells for neural repair—factors that promote neurogenesis and gliogenesis in the normal and damaged brain

PubMed Central

Christie, Kimberly J.; Turnley, Ann M.

2012-01-01

Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation. PMID:23346046

Neural Stem Cells Derived Directly from Adipose Tissue.

PubMed

Petersen, Eric D; Zenchak, Jessica R; Lossia, Olivia V; Hochgeschwender, Ute

2018-05-01

Neural stem cells (NSCs) are characterized as self-renewing cell populations with the ability to differentiate into the multiple tissue types of the central nervous system. These cells can differentiate into mature neurons, astrocytes, and oligodendrocytes. This category of stem cells has been shown to be a promisingly effective treatment for neurodegenerative diseases and neuronal injury. Most treatment studies with NSCs in animal models use embryonic brain-derived NSCs. This approach presents both ethical and feasibility issues for translation to human patients. Adult tissue is a more practical source of stem cells for transplantation therapies in humans. Some adult tissues such as adipose tissue and bone marrow contain a wide variety of stem cell populations, some of which have been shown to be similar to embryonic stem cells, possessing many pluripotent properties. Of these stem cell populations, some are able to respond to neuronal growth factors and can be expanded in vitro, forming neurospheres analogous to cells harvested from embryonic brain tissue. In this study, we describe a method for the collection and culture of cells from adipose tissue that directly, without going through intermediates such as mesenchymal stem cells, results in a population of NSCs that are able to be expanded in vitro and be differentiated into functional neuronal cells. These adipose-derived NSCs display a similar phenotype to those directly derived from embryonic brain. When differentiated into neurons, cells derived from adipose tissue have spontaneous spiking activity with network characteristics similar to that of neuronal cultures.

Experimental high-velocity missile head injury.

PubMed

Allen, I V; Scott, R; Tanner, J A

1982-09-01

A standardized experimental high-velocity penetrating head-injury model has been produced in which pathological lesions were observed, not only in the wound track but at sites more remote from the track in the hypothalamus, brain stem and cerebellum. Diffuse subarachnoid haemorrhage was common and intraventricular haemorrhage was a constant feature. Other constant histological abnormalities were:L 1. Perivascular "ring' haemorrhages. 2. Perivascular haemorrhage with a surrounding zone of decreased staining intensity. 3. Perivascular increased staining intensity. 4. Areas of decreased staining intensity apparently dissociated from areas of haemorrhage. The pathogenesis of the perivascular lesions is discussed and preliminary studies suggest that these may be the site of early oedema. The implications of this experiment for military surgery and for ballistic protection of the head are discussed.

TGFβ lengthens the G1 phase of stem cells in aged mouse brain.

PubMed

Daynac, Mathieu; Pineda, Jose R; Chicheportiche, Alexandra; Gauthier, Laurent R; Morizur, Lise; Boussin, François D; Mouthon, Marc-André

2014-12-01

Neurogenesis decreases during aging causing a progressive cognitive decline but it is still controversial whether proliferation defects in neurogenic niches result from a loss of neural stem cells or from an impairment of their progression through the cell cycle. Using an accurate fluorescence-activated cell sorting technique, we show that the pool of neural stem cells is maintained in the subventricular zone of middle-aged mice while they have a reduced proliferative potential eventually leading to the subsequent decrease of their progeny. In addition, we demonstrate that the G1 phase is lengthened during aging specifically in activated stem cells, but not in transit-amplifying cells, and directly impacts on neurogenesis. Finally, we report that inhibition of TGFβ signaling restores cell cycle progression defects in stem cells. Our data highlight the significance of cell cycle dysregulation in stem cells in the aged brain and provide an attractive foundation for the development of anti-TGFβ regenerative therapies based on stimulating endogenous neural stem cells. © 2014 AlphaMed Press.

A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination.

PubMed

Zhao, Chunnian; Sun, GuoQiang; Li, Shengxiu; Shi, Yanhong

2009-04-01

MicroRNAs have been implicated as having important roles in stem cell biology. MicroRNA-9 (miR-9) is expressed specifically in neurogenic areas of the brain and may be involved in neural stem cell self-renewal and differentiation. We showed previously that the nuclear receptor TLX is an essential regulator of neural stem cell self-renewal. Here we show that miR-9 suppresses TLX expression to negatively regulate neural stem cell proliferation and accelerate neural differentiation. Introducing a TLX expression vector that is not prone to miR-9 regulation rescued miR-9-induced proliferation deficiency and inhibited precocious differentiation. In utero electroporation of miR-9 in embryonic brains led to premature differentiation and outward migration of the transfected neural stem cells. Moreover, TLX represses expression of the miR-9 pri-miRNA. By forming a negative regulatory loop with TLX, miR-9 provides a model for controlling the balance between neural stem cell proliferation and differentiation.

A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination

PubMed Central

Zhao, Chunnian; Sun, GuoQiang; Li, Shengxiu; Shi, Yanhong

2009-01-01

Summary MicroRNAs are important players in stem cell biology. Among them, microRNA-9 (miR-9) is expressed specifically in neurogenic areas of the brain. Whether miR-9 plays a role in neural stem cell self-renewal and differentiation is unknown. We showed previously that nuclear receptor TLX is an essential regulator of neural stem cell self-renewal. Here we show that miR-9 suppresses TLX expression to negatively regulate neural stem cell proliferation and accelerate neural differentiation. Introducing a TLX expression vector lacking the miR-9 recognition site rescued miR-9-induced proliferation deficiency and inhibited precocious differentiation. In utero electroporation of miR-9 in embryonic brains led to premature differentiation and outward migration of the transfected neural stem cells. Moreover, TLX represses miR-9 pri-miRNA expression. MiR-9, by forming a negative regulatory loop with TLX, establishes a model for controlling the balance between neural stem cell proliferation and differentiation. PMID:19330006

Gelatinized Copper–Capillary Alginate Gel Functions as an Injectable Tissue Scaffolding System for Stem Cell Transplants

PubMed Central

Willenberg, Bradley Jay; Zheng, Tong; Meng, Fan-Wei; Meneses, Juan Carlos; Rossignol, Candace; Batich, Christopher D.; Terada, Naohiro; Steindler, Dennis A.; Weiss, Michael D.

2013-01-01

In severe hypoxic–ischemic brain injury, cellular components such as neurons and astrocytes are injured or destroyed along with the supporting extracellular matrix. This presents a challenge to the field of regenerative medicine since the lack of extracellular matrix and supporting structures makes the transplant milieu inhospitable to the transplanted cells. A potential solution to this problem is the use of a biomaterial to provide the extracellular components needed to keep cells localized in cystic brain regions, allowing the cells to form connections and repair lost brain tissue. Ideally, this biomaterial would be combined with stem cells, which have been proven to have therapeutic potentials, and could be delivered via an injection. To study this approach, we derived a hydrogel biomaterial tissue scaffold from oligomeric gelatin and copper–capillary alginate gel (GCCAG). We then demonstrated that our multipotent astrocytic stem cells (MASCs) could be maintained in GCCAG scaffolds for up to 2 weeks in vitro and that the cells retained their multipotency. We next performed a pilot transplant study in which GCCAG was mixed with MASCs and injected into the brain of a neonatal rat pup. After a week in vivo, our results showed that: the GCCAG biomaterial did not cause a significant reactive gliosis; viable cells were retained within the injected scaffolds; and some delivered cells migrated into the surrounding brain tissue. Therefore, GCCAG tissue scaffolds are a promising, novel injectable system for transplantation of stem cells to the brain. PMID:20699061

Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome‐wide expression analysis

PubMed Central

Sirko, Swetlana; Beckers, Johannes; Irmler, Martin

2015-01-01

Here, we review the stem cell hallmarks of endogenous neural stem cells (NSCs) during development and in some niches of the adult mammalian brain to then compare these with reactive astrocytes acquiring stem cell hallmarks after traumatic and ischemic brain injury. Notably, even endogenous NSCs including the earliest NSCs, the neuroepithelial cells, generate in most cases only a single type of progeny and self‐renew only for a rather short time in vivo. In vitro, however, especially cells cultured under neurosphere conditions reveal a larger potential and long‐term self‐renewal under the influence of growth factors. This is rather well comparable to reactive astrocytes in the traumatic or ischemic brain some of which acquire neurosphere‐forming capacity including multipotency and long‐term self‐renewal in vitro, while they remain within their astrocyte lineage in vivo. Both reactive astrocytes and endogenous NSCs exhibit stem cell hallmarks largely in vitro, but their lineage differs in vivo. Both populations generate largely a single cell type in vivo, but endogenous NSCs generate neurons and reactive astrocytes remain in the astrocyte lineage. However, at some early postnatal stages or in some brain regions reactive astrocytes can be released from this fate restriction, demonstrating that they can also enact neurogenesis. Thus, reactive astrocytes and NSCs share many characteristic hallmarks, but also exhibit key differences. This conclusion is further substantiated by genome‐wide expression analysis comparing NSCs at different stages with astrocytes from the intact and injured brain parenchyma. GLIA 2015;63:1452–1468 PMID:25965557

Regional variations and age-related changes in arginine metabolism in the rat brain stem and spinal cord.

PubMed

Jing, Y; Fleete, M S; Collie, N D; Zhang, H; Liu, P

2013-11-12

Accumulating evidence suggests that the metabolism of l-arginine, a metabolically versatile amino acid, is critically involved in the aging process. The present study compared the activity and protein expression of nitric oxide synthase (NOS) and arginase, and the levels of l-arginine and its eight down-stream metabolites in the brain stem (pons and medulla) and the cervical spinal cord in 3- (young) and 22- (aged) month-old male Sprague-Dawley rats. Total NOS activity was significantly reduced with age in the spinal cord (but not brain stem), and there were no age-related changes in arginase activity in both regions. Western blot revealed decreased protein expression of endothelial NOS, but not neuronal NOS, with age in both regions. Furthermore, there were significantly decreased l-arginine, glutamate, GABA and spermine levels and increased putrescine and spermidine levels with age in both regions. Although the absolute concentrations of l-arginine and six metabolites were significantly different between the brain stem and spinal cord in both age groups, there were similar clusters between l-arginine and its three main metabolites (l-citrulline, l-ornithine and agmatine) in both regions, which changed as a function of age. These findings, for the first time, demonstrate the regional variations and age-related changes in arginine metabolism in the rat brain stem and spinal cord. Future research is required to understand the functional significance of these changes and the underlying mechanisms. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation

PubMed Central

Lundblad, Linda C.; Fatouleh, Rania H.; McKenzie, David K.; Macefield, Vaughan G.

2015-01-01

Obstructive sleep apnea (OSA) is associated with significantly elevated muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. Although little is known about the mechanisms responsible for the sympathoexcitation, we have recently shown that the elevated MSNA in OSA is associated with altered neural processing in various brain stem sites, including the dorsolateral pons, rostral ventrolateral medulla, medullary raphe, and midbrain. Given the risk associated with elevated MSNA, we aimed to determine if treatment of OSA with continuous positive airway pressure (CPAP) would reduce the elevated MSNA and reverse the brain stem functional changes associated with the elevated MSNA. We performed concurrent recordings of MSNA and blood oxygen level-dependent (BOLD) signal intensity of the brain stem, using high-resolution functional magnetic resonance imaging, in 15 controls and 13 subjects with OSA, before and after 6 mo CPAP treatment. As expected, 6 mo of CPAP treatment significantly reduced MSNA in subjects with OSA, from 54 ± 4 to 23 ± 3 bursts/min and from 77 ± 7 to 36 ± 3 bursts/100 heart beats. Importantly, we found that MSNA-coupled changes in BOLD signal intensity within the dorsolateral pons, medullary raphe, and rostral ventrolateral medulla returned to control levels. That is, CPAP treatment completely reversed brain stem functional changes associated with elevated MSNA in untreated OSA subjects. These data highlight the effectiveness of CPAP treatment in reducing one of the most significant health issues associated with OSA, that is, elevated MSNA and its associated elevated morbidity. PMID:25995345

Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation.

PubMed

Lundblad, Linda C; Fatouleh, Rania H; McKenzie, David K; Macefield, Vaughan G; Henderson, Luke A

2015-08-01

Obstructive sleep apnea (OSA) is associated with significantly elevated muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. Although little is known about the mechanisms responsible for the sympathoexcitation, we have recently shown that the elevated MSNA in OSA is associated with altered neural processing in various brain stem sites, including the dorsolateral pons, rostral ventrolateral medulla, medullary raphe, and midbrain. Given the risk associated with elevated MSNA, we aimed to determine if treatment of OSA with continuous positive airway pressure (CPAP) would reduce the elevated MSNA and reverse the brain stem functional changes associated with the elevated MSNA. We performed concurrent recordings of MSNA and blood oxygen level-dependent (BOLD) signal intensity of the brain stem, using high-resolution functional magnetic resonance imaging, in 15 controls and 13 subjects with OSA, before and after 6 mo CPAP treatment. As expected, 6 mo of CPAP treatment significantly reduced MSNA in subjects with OSA, from 54 ± 4 to 23 ± 3 bursts/min and from 77 ± 7 to 36 ± 3 bursts/100 heart beats. Importantly, we found that MSNA-coupled changes in BOLD signal intensity within the dorsolateral pons, medullary raphe, and rostral ventrolateral medulla returned to control levels. That is, CPAP treatment completely reversed brain stem functional changes associated with elevated MSNA in untreated OSA subjects. These data highlight the effectiveness of CPAP treatment in reducing one of the most significant health issues associated with OSA, that is, elevated MSNA and its associated elevated morbidity. Copyright © 2015 the American Physiological Society.

Modules in the brain stem and spinal cord underlying motor behaviors

PubMed Central

Cheung, Vincent C. K.; Bizzi, Emilio

2011-01-01

Previous studies using intact and spinalized animals have suggested that coordinated movements can be generated by appropriate combinations of muscle synergies controlled by the central nervous system (CNS). However, which CNS regions are responsible for expressing muscle synergies remains an open question. We address whether the brain stem and spinal cord are involved in expressing muscle synergies used for executing a range of natural movements. We analyzed the electromyographic (EMG) data recorded from frog leg muscles before and after transection at different levels of the neuraxis—rostral midbrain (brain stem preparations), rostral medulla (medullary preparations), and the spinal-medullary junction (spinal preparations). Brain stem frogs could jump, swim, kick, and step, while medullary frogs could perform only a partial repertoire of movements. In spinal frogs, cutaneous reflexes could be elicited. Systematic EMG analysis found two different synergy types: 1) synergies shared between pre- and posttransection states and 2) synergies specific to individual states. Almost all synergies found in natural movements persisted after transection at rostral midbrain or medulla but not at the spinal-medullary junction for swim and step. Some pretransection- and posttransection-specific synergies for a certain behavior appeared as shared synergies for other motor behaviors of the same animal. These results suggest that the medulla and spinal cord are sufficient for the expression of most muscle synergies in frog behaviors. Overall, this study provides further evidence supporting the idea that motor behaviors may be constructed by muscle synergies organized within the brain stem and spinal cord and activated by descending commands from supraspinal areas. PMID:21653716

Brain Stem Infarction Due to Basilar Artery Dissection in a Patient with Moyamoya Disease Four Years after Successful Bilateral Revascularization Surgeries.

PubMed

Abe, Takatsugu; Fujimura, Miki; Mugikura, Shunji; Endo, Hidenori; Tominaga, Teiji

2016-06-01

Moyamoya disease (MMD) is a rare cerebrovascular disease with an unknown etiology and is characterized by intrinsic fragility in the intracranial vascular walls such as the affected internal elastic lamina and thinning medial layer. The association of MMD with intracranial arterial dissection is extremely rare, whereas that with basilar artery dissection (BAD) has not been reported previously. A 46-year-old woman developed brain stem infarction due to BAD 4 years after successful bilateral superficial temporal artery-middle cerebral artery anastomosis with indirect pial synangiosis for ischemic-onset MMD. She presented with sudden occipitalgia and subsequently developed transient dysarthria and mild hemiparesis. Although a transient ischemic attack was initially suspected, her condition deteriorated in a manner that was consistent with left hemiplegia with severe dysarthria. Magnetic resonance (MR) imaging revealed brain stem infarction, and MR angiography delineated a double-lumen sign in the basilar artery, indicating BAD. She was treated conservatively and brain stem infarction did not expand. One year after the onset of brain stem infarction, her activity of daily living is still dependent (modified Rankin Scale of 4), and there were no morphological changes associated with BAD or recurrent cerebrovascular events during the follow-up period. The association of MMD with BAD is extremely rare. While considering the common underlying pathology such as an affected internal elastic lamina and fragile medial layer, the occurrence of BAD in a patient with MMD in a stable hemodynamic state is apparently unique. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Analysis of wave III of brain stem auditory evoked potential waveforms during microvascular decompression of cranial nerve VII for hemifacial spasm.

PubMed

Thirumala, Parthasarathy D; Krishnaiah, Balaji; Crammond, Donald J; Habeych, Miguel E; Balzer, Jeffrey R

2014-04-01

Intraoperative monitoring of brain stem auditory evoked potential during microvascular decompression (MVD) prevent hearing loss (HL). Previous studies have shown that changes in wave III (wIII) are an early and sensitive sign of auditory nerve injury. To evaluate the changes of amplitude and latency of wIII of brain stem auditory evoked potential during MVD and its association with postoperative HL. Hearing loss was classified by American Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) criteria, based on changes in pure tone audiometry and speech discrimination score. Retrospective analysis of wIII in patients who underwent intraoperative monitoring with brain stem auditory evoked potential during MVD was performed. A univariate logistic regression analysis was performed on independent variables amplitude of wIII and latency of wIII at change max and On-Skin, or a final recording at the time of skin closure. A further analysis for the same variables was performed adjusting for the loss of wave. The latency of wIII was not found to be significantly different between groups I and II. The amplitude of wIII was significantly decreased in the group with HL. Regression analysis did not find any increased odds of HL with changes in the amplitude of wIII. Changes in wave III did not increase the odds of HL in patients who underwent brain stem auditory evoked potential s during MVD. This information might be valuable to evaluate the value of wIII as an alarm criterion during MVD to prevent HL.

Effect of Mobile Phone-Induced Electromagnetic Field on Brain Hemodynamics and Human Stem Cell Functioning: Possible Mechanistic Link to Cancer Risk and Early Diagnostic Value of Electronphotonic Imaging.

PubMed

Bhargav, Hemant; Srinivasan, T M; Varambally, S; Gangadhar, B N; Koka, Prasad

2015-01-01

The mobile phones (MP) are low power radio devices which work on electromagnetic fields (EMFs), in the frequency range of 900-1800 MHz. Exposure to MPEMFs may affect brain physiology and lead to various health hazards including brain tumors. Earlier studies with positron emission tomography (PET) have found alterations in cerebral blood flow (CBF) after acute exposure to MPEMFs. It is widely accepted that DNA double-strand breaks (DSBs) and their misrepair in stem cells are critical events in the multistage origination of various leukemia and tumors, including brain tumors such as gliomas. Both significant misbalance in DSB repair and severe stress response have been triggered by MPEMFs and EMFs from cell towers. It has been shown that stem cells are most sensitive to microwave exposure and react to more frequencies than do differentiated cells. This may be important for cancer risk assessment and indicates that stem cells are the most relevant cellular model for validating safe mobile communication signals. Recently developed technology for recording the human bio-electromagnetic (BEM) field using Electron photonic Imaging (EPI) or Gas Discharge Visualisation (GDV) technique provides useful information about the human BEM. Studies have recorded acute effects of Mobile Phone Electromagnetic Fields (MPEMFs) using EPI and found quantifiable effects on human BEM field. Present manuscript reviews evidences of altered brain physiology and stem cell functioning due to mobile phone/cell tower radiations, its association with increased cancer risk and explores early diagnostic value of EPI imaging in detecting EMF induced changes on human BEM.

Biomechanics of Concussion: The Importance of Neck Tension

NASA Astrophysics Data System (ADS)

Jadischke, Ronald

Linear and angular velocity and acceleration of the head are typically correlated to concussion. Despite improvements in helmet performance to reduce accelerations, a corresponding reduction in the incidence of concussion has not occurred (National Football League [NFL] 1996-present). There is compelling research that forces on and deformation to the brain stem are related to concussion. The brain stem is the center of control for respiration, blood pressure and heart rate and is the root of most cranial nerves. Injury to the brain stem is consistent with most symptoms of concussion reported in the National Football League and the National Hockey League, such as headaches, neck pain, dizziness, and blurred vision. In the Hybrid III anthropomorphic test device (ATD), the upper neck load cell is in close proximity to the human brain stem. This study found that the additional mass of a football helmet onto the Hybrid III headform increases the upper neck forces and moments in response to helmet-to-helmet impact and helmet-to-chest impacts. A new laboratory impactor device was constructed to simulate collisions using two moving Hybrid III ATDs. The impactor was used to recreate on-field collisions (n = 20) in American football while measuring head, neck and upper torso kinematics. A strong correlation between upper neck forces, upper neck power and the estimated strains and strain rates along the axis of the upper cervical spinal cord and brain stem and concussion was found. These biomechanical responses should be added to head kinematic responses for a more comprehensive evaluation of concussion.

Spatio-temporal neural stem cell behavior that leads to both perfect and imperfect structural brain regeneration in adult newts.

PubMed

Urata, Yuko; Yamashita, Wataru; Inoue, Takeshi; Agata, Kiyokazu

2018-06-14

Adult newts can regenerate large parts of their brain from adult neural stem cells (NSCs), but how adult NSCs reorganize brain structures during regeneration remains unclear. In development, elaborate brain structures are produced under broadly coordinated regulations of embryonic NSCs in the neural tube, whereas brain regeneration entails exquisite control of the reestablishment of certain brain parts, suggesting a yet-unknown mechanism directs NSCs upon partial brain excision. Here we report that upon one-quarter excision of the adult newt ( Pleurodeles waltl ) mesencephalon, active participation of local NSCs around specific brain subregions' boundaries leads to some imperfect and some perfect brain regeneration along an individual's rostrocaudal axis. Regeneration phenotypes depend on how the wound closing occurs using local NSCs, and perfect regeneration replicates development-like processes but takes more than one year. Our findings indicate that newt brain regeneration is supported by modularity of boundary-domain NSCs with self-organizing ability in neighboring fields. © 2018. Published by The Company of Biologists Ltd.

Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats.

PubMed

Amini, Naser; Vousooghi, Nasim; Hadjighassem, Mahmoudreza; Bakhtiyari, Mehrdad; Mousavi, Neda; Safakheil, Hosein; Jafari, Leila; Sarveazad, Arash; Yari, Abazar; Ramezani, Sara; Faghihi, Faezeh; Joghataei, Mohammad Taghi

2016-05-01

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.

Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals

USDA-ARS?s Scientific Manuscript database

The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularize...

Harnessing Autopsied DIPG Tumor Tissues for Orthotopic Xenograft Model Development in the Brain Stems of SCID Mice

DTIC Science & Technology

2012-09-01

patched-1-deficient mouse medulloblastoma . Cancer Res. 2009;69:4682-4690. 14. Mao XG, Zhang X, Xue XY, et al. Brain Tumor Stem-Like Cells Identified by...propagating cells in a mouse model of medulloblastoma . Cancer Cell. 2009;15:135-147. 16. Yagi H, Yanagisawa M, Suzuki Y, et al. HNK-1 epitope-carrying

A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

PubMed

Cecchelli, Romeo; Aday, Sezin; Sevin, Emmanuel; Almeida, Catarina; Culot, Maxime; Dehouck, Lucie; Coisne, Caroline; Engelhardt, Britta; Dehouck, Marie-Pierre; Ferreira, Lino

2014-01-01

The human blood brain barrier (BBB) is a selective barrier formed by human brain endothelial cells (hBECs), which is important to ensure adequate neuronal function and protect the central nervous system (CNS) from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs) express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis.

PubMed

Saito, Kanako; Dubreuil, Veronique; Arai, Yoko; Wilsch-Bräuninger, Michaela; Schwudke, Dominik; Saher, Gesine; Miyata, Takaki; Breier, Georg; Thiele, Christoph; Shevchenko, Andrej; Nave, Klaus-Armin; Huttner, Wieland B

2009-05-19

Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5-E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1-independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis.

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

PubMed Central

Saito, Kanako; Dubreuil, Veronique; Arai, Yoko; Wilsch-Bräuninger, Michaela; Schwudke, Dominik; Saher, Gesine; Miyata, Takaki; Breier, Georg; Thiele, Christoph; Shevchenko, Andrej; Nave, Klaus-Armin; Huttner, Wieland B.

2009-01-01

Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5–E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1–independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis. PMID:19416849

The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone

PubMed Central

Liu, Hai-Kun; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Wu, Hui; Lichter, Peter; Chai, Minqiang; Schütz, Günther

2008-01-01

The tailless (Tlx) gene encodes an orphan nuclear receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). The function of Tlx in neural stem cells of the adult SVZ remains largely unknown. We show here that in the SVZ of the adult brain Tlx is exclusively expressed in astrocyte-like B cells. An inducible mutation of the Tlx gene in the adult brain leads to complete loss of SVZ neurogenesis. Furthermore, analysis indicates that Tlx is required for the transition from radial glial cells to astrocyte-like neural stem cells. These findings demonstrate the crucial role of Tlx in the generation and maintenance of NSCs in the adult SVZ in vivo. PMID:18794344

[Perspectives of cell therapy in sequelae from cerebrovascular accidents].

PubMed

Otero, Laura; Zurita, Mercedes; Bonilla, Celia; Aguayo, Concepción; Rico, Miguel Angel; Vaquero, Jesús

2012-09-01

Spontaneous intracerebral hemorrhage (ICH) is associated with mortality between 40 and 50% of cases. Among the survivors, only 10% are independent after one month, there is no effective treatment of sequelae, except for the limited possibilities providing for rehabilitation. We review the current experience with intracerebral transplantation of mesenchymal stem cells (MSCs) obtained from bone marrow as a potential treatment of neurological sequelae occurring after experimental ICH. We describe the model of ICH by intracerebral administration of collagenaseIV at basal ganglia level in Wistar rats. Neurological deficits caused by ICH can be quantified through a variety of functional assessment test (NMSS, Rota-rod, VTB-test). 5×10allogeneic MSCs in 10μl of saline were administered intracerebrally in 10 animals, 2 months after ICH. In another 10 animals (controls) the same volume of saline was administered. Changes in the functional deficits were assessed during the next 6 months in both experimental groups. The results suggested therapeutic efficacy of MSCs transplantation and showed that transplanted stem cells can survive in the injured brain, transforming into neurons and glial cells. This form of cell therapy induces reactivation of endogenous neurogenesis at the subventricular zone (SVZ) and achieves antiapoptotic protective effect in the injured brain. Cell therapy represents an important field of research with potential clinical application to treatment of neurological sequels, currently considered irreversible. Neurosurgeons should become involved in the development of these new techniques that are likely to shape the future of this specialty. Copyright © 2011 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury

PubMed Central

2013-01-01

Background Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model. Methods/results MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway. Conclusions The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI. PMID:23971414

Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury.

PubMed

Ghazale, Hussein; Ramadan, Naify; Mantash, Sara; Zibara, Kazem; El-Sitt, Sally; Darwish, Hala; Chamaa, Farah; Boustany, Rose Mary; Mondello, Stefania; Abou-Kheir, Wassim; Soueid, Jihane; Kobeissy, Firas

2018-03-15

Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa αII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI. Copyright © 2017 Elsevier B.V. All rights reserved.

Deregulated proliferation and differentiation in brain tumors

PubMed Central

Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

2014-01-01

Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

Brain-Derived Neurotrophic Factor Increases Synaptic Protein Levels via the MAPK/Erk Signaling Pathway and Nrf2/Trx Axis Following the Transplantation of Neural Stem Cells in a Rat Model of Traumatic Brain Injury.

PubMed

Chen, Tao; Wu, Yu; Wang, Yuzi; Zhu, Jigao; Chu, Haiying; Kong, Li; Yin, Liangwei; Ma, Haiying

2017-11-01

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting the growth, differentiation, survival and synaptic stability of neurons. Presently, the transplantation of neural stem cells (NSCs) is known to induce neural repair to some extent after injury or disease. In this study, to investigate whether NSCs genetically modified to encode the BDNF gene (BDNF/NSCs) would further enhance synaptogenesis, BDNF/NSCs or naive NSCs were directly engrafted into lesions in a rat model of traumatic brain injury (TBI). Immunohistochemistry, western blotting and RT-PCR were performed to detect synaptic proteins, BDNF-TrkB and its downstream signaling pathways, at 1, 2, 3 or 4 weeks after transplantation. Our results showed that BDNF significantly increased the expression levels of the TrkB receptor gene and the phosphorylation of the TrkB protein in the lesions. The expression levels of Ras, phosphorylated Erk1/2 and postsynaptic density protein-95 were elevated in the BDNF/NSCs-transplanted groups compared with those in the NSCs-transplanted groups throughout the experimental period. Moreover, the nuclear factor (erythroid-derived 2)-like 2/Thioredoxin (Nrf2/Trx) axis, which is a specific therapeutic target for the treatment of injury or cell death, was upregulated by BDNF overexpression. Therefore, we determined that the increased synaptic proteins level implicated in synaptogenesis might be associated with the activation of the MAPK/Erk1/2 signaling pathway and the upregulation of the antioxidant agent Trx modified by BDNF-TrkB following the BDNF/NSCs transplantation after TBI.

New molecules and old drugs as emerging approaches to selectively target human glioblastoma cancer stem cells.

PubMed

Würth, Roberto; Barbieri, Federica; Florio, Tullio

2014-01-01

Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM), the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.

The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells.

PubMed

Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Nam, Do-Hyun; Kim, Hyunggee

2010-11-01

A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.

Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration.

PubMed

Kaslin, Jan; Kroehne, Volker; Ganz, Julia; Hans, Stefan; Brand, Michael

2017-04-15

Zebrafish can regenerate after brain injury, and the regenerative process is driven by resident stem cells. Stem cells are heterogeneous in the vertebrate brain, but the significance of having heterogeneous stem cells in regeneration is not understood. Limited availability of specific stem cells might impair the regeneration of particular cell lineages. We studied regeneration of the adult zebrafish cerebellum, which contains two major stem and progenitor cell types: ventricular zone and neuroepithelial cells. Using conditional lineage tracing we demonstrate that cerebellar regeneration depends on the availability of specific stem cells. Radial glia-like cells are thought to be the predominant stem cell type in homeostasis and after injury. However, we find that radial glia-like cells play a minor role in adult cerebellar neurogenesis and in recovery after injury. Instead, we find that neuroepithelial cells are the predominant stem cell type supporting cerebellar regeneration after injury. Zebrafish are able to regenerate many, but not all, cell types in the cerebellum, which emphasizes the need to understand the contribution of different adult neural stem and progenitor cell subtypes in the vertebrate central nervous system. © 2017. Published by The Company of Biologists Ltd.

Ethical and medical management of a pregnant woman with brain stem death resulting in delivery of a healthy child and organ donation.

PubMed

Gopčević, A; Rode, B; Vučić, M; Horvat, A; Širanović, M; Gavranović, Ž; Košec, V; Košec, A

2017-11-01

Maternal brain death during pregnancy remains an exceedingly complex situation that requires not only a well-considered medical management plan, but also careful decision-making in a legally and ethically delicate situation. Management of brain dead pregnant patients needs to adhere to special strategies that support the mother in a way that she can deliver a viable and healthy child. Brain death in pregnant women is very rare, with only a few published cases. We present a case of a pregnant woman with previously diagnosed multiple brain cavernomas that led to intracranial hemorrhage and brain stem death during the 21st week of pregnancy. The condition that can be proven unequivocally, using tests that do not endanger viability of the fetus, is brain stem death, diagnosed through absence of cranial reflexes. The patient was successfully treated until delivery of a healthy female child at 29weeks of gestation. The patient received continuous hormone substitution therapy, fetal monitoring and extrinsic regulation of maternal homeostasis over 64days. After delivery, the final diagnosis of brain death was established through multi-slice computerized tomography pan-angiography. This challenging case discusses ethical and medical circumstances arising from a diagnosis of maternal brain death, while showing that prolongation of somatic life support in a multidisciplinary setting can result in a successful pregnancy outcome. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative transcriptome analysis in induced neural stem cells reveals defined neural cell identities in vitro and after transplantation into the adult rodent brain.

PubMed

Hallmann, Anna-Lena; Araúzo-Bravo, Marcos J; Zerfass, Christina; Senner, Volker; Ehrlich, Marc; Psathaki, Olympia E; Han, Dong Wook; Tapia, Natalia; Zaehres, Holm; Schöler, Hans R; Kuhlmann, Tanja; Hargus, Gunnar

2016-05-01

Reprogramming technology enables the production of neural progenitor cells (NPCs) from somatic cells by direct transdifferentiation. However, little is known on how neural programs in these induced neural stem cells (iNSCs) differ from those of alternative stem cell populations in vitro and in vivo. Here, we performed transcriptome analyses on murine iNSCs in comparison to brain-derived neural stem cells (NSCs) and pluripotent stem cell-derived NPCs, which revealed distinct global, neural, metabolic and cell cycle-associated marks in these populations. iNSCs carried a hindbrain/posterior cell identity, which could be shifted towards caudal, partially to rostral but not towards ventral fates in vitro. iNSCs survived after transplantation into the rodent brain and exhibited in vivo-characteristics, neural and metabolic programs similar to transplanted NSCs. However, iNSCs vastly retained caudal identities demonstrating cell-autonomy of regional programs in vivo. These data could have significant implications for a variety of in vitro- and in vivo-applications using iNSCs. Copyright © 2016 Roslin Cells Ltd. Published by Elsevier B.V. All rights reserved.

Descending pathways to the cutaneus trunci muscle motoneuronal cell group in the cat

NASA Technical Reports Server (NTRS)

Holstege, Gert; Blok, Bertil F.

1989-01-01

Pathways involved in the cutaneous trunci muscle (CTM) reflex in the cat were investigated. Experimental animals were injected with tritium-labeled L-leucine into their spinal cord, brain stem, or diencephalon and, after six weeks, perfused with 10-percent formalin. The brains and spinal cords were postfixed in formalin and were cut into transverse 25-micron-thick frozen sections for autoradiography. Results based on injections in the C1, C2, C6, and C8 segments suggest that propriospinal pathways to the CTM motor nucleus originating in the cervical cord do no exist, although these propriospinal projections are very strong to all other motoneuronal cell groups surrounding the CTM motor nucleus. The results also demonstrate presence of specific supraspinal projections to the CTM motor nucleus, originating in the contralateral nucleus retroambiguous and the ipsilateral dorsolateral pontine tegmentum.

Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers

PubMed Central

Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

2014-01-01

Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step‐and‐shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose <45 Gy to spinal cord and <50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5±2.2 Gy and 36.7±14.0 Gy), without significant changes on the other OARs. A marked difference (−15.9±1.9 Gy and −10.1±5.7 Gy) was obtained at the expense of a small difference (−1.3%±0.9%) from initial PTV195% coverage (96.6%±0.9%). Similar difference (−15.7±2.2 Gy and −10.2±6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (−0.3%±0.3% from the initial 98.3%±0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer. PACS number: 87.55.D PMID:24423836

Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells

PubMed Central

Podergajs, Neža; Motaln, Helena; Rajčević, Uroš; Verbovšek, Urška; Koršič, Marjan; Obad, Nina; Espedal, Heidi; Vittori, Miloš; Herold-Mende, Christel; Miletic, Hrvoje; Bjerkvig, Rolf; Turnšek, Tamara Lah

2016-01-01

The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment. PMID:26573230

Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells.

PubMed

Yan, Yiping; Shin, Soojung; Jha, Balendu Shekhar; Liu, Qiuyue; Sheng, Jianting; Li, Fuhai; Zhan, Ming; Davis, Janine; Bharti, Kapil; Zeng, Xianmin; Rao, Mahendra; Malik, Nasir; Vemuri, Mohan C

2013-11-01

Human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, are unique cell sources for disease modeling, drug discovery screens, and cell therapy applications. The first step in producing neural lineages from hPSCs is the generation of neural stem cells (NSCs). Current methods of NSC derivation involve the time-consuming, labor-intensive steps of an embryoid body generation or coculture with stromal cell lines that result in low-efficiency derivation of NSCs. In this study, we report a highly efficient serum-free pluripotent stem cell neural induction medium that can induce hPSCs into primitive NSCs (pNSCs) in 7 days, obviating the need for time-consuming, laborious embryoid body generation or rosette picking. The pNSCs expressed the neural stem cell markers Pax6, Sox1, Sox2, and Nestin; were negative for Oct4; could be expanded for multiple passages; and could be differentiated into neurons, astrocytes, and oligodendrocytes, in addition to the brain region-specific neuronal subtypes GABAergic, dopaminergic, and motor neurons. Global gene expression of the transcripts of pNSCs was comparable to that of rosette-derived and human fetal-derived NSCs. This work demonstrates an efficient method to generate expandable pNSCs, which can be further differentiated into central nervous system neurons and glia with temporal, spatial, and positional cues of brain regional heterogeneity. This method of pNSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions.

Exposure to Organophosphates Reduces the Expression of Neurotrophic Factors in Neonatal Rat Brain Regions: Similarities and Differences in the Effects of Chlorpyrifos and Diazinon on the Fibroblast Growth Factor Superfamily

PubMed Central

Slotkin, Theodore A.; Seidler, Frederic J.; Fumagalli, Fabio

2007-01-01

Background The fibroblast growth factor (FGF) superfamily of neurotrophic factors plays critical roles in neural cell development, brain assembly, and recovery from neuronal injury. Objectives We administered two organophosphate pesticides, chlorpyrifos and diazinon, to neonatal rats on postnatal days 1–4, using doses below the threshold for systemic toxicity or growth impairment, and spanning the threshold for barely detectable cholinesterase inhibition: 1 mg/kg/day chlorpyrifos and 1 or 2 mg/kg/day diazinon. Methods Using microarrays, we then examined the regional expression of mRNAs encoding the FGFs and their receptors (FGFRs) in the forebrain and brain stem. Results Chlorpyrifos and diazinon both markedly suppressed fgf20 expression in the forebrain and fgf2 in the brain stem, while elevating brain stem fgfr4 and evoking a small deficit in brain stem fgf22. However, they differed in that the effects on fgf2 and fgfr4 were significantly larger for diazinon, and the two agents also showed dissimilar, smaller effects on fgf11, fgf14, and fgfr1. Conclusions The fact that there are similarities but also notable disparities in the responses to chlorpyrifos and diazinon, and that robust effects were seen even at doses that do not inhibit cholinesterase, supports the idea that organophosphates differ in their propensity to elicit developmental neurotoxicity, unrelated to their anticholinesterase activity. Effects on neurotrophic factors provide a mechanistic link between organophosphate injury to developing neurons and the eventual, adverse neurodevelopmental outcomes. PMID:17589599

Role of the brain stem in tibial inhibition of the micturition reflex in cats.

PubMed

Ferroni, Matthew C; Slater, Rick C; Shen, Bing; Xiao, Zhiying; Wang, Jicheng; Lee, Andy; Roppolo, James R; de Groat, William C; Tai, Changfeng

2015-08-01

This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in α-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (>2 h) poststimulation inhibition that significantly (P < 0.05) increased bladder capacity to 30-60% above control; however, TNS did not produce this effect during AA irritation. TNS applied during CMGs at 5 Hz but not 30 Hz significantly (P < 0.01) increased bladder capacity to 127.3 ± 6.1% of saline control or 187.6 ± 5.0% of AA control. During AA irritation, naloxone (an opioid receptor antagonist) administered intravenously (1 mg/kg) or directly to the surface of the rostral brain stem (300-900 μg) eliminated acute TNS inhibition and significantly (P < 0.05) reduced bladder capacity to 62.8 ± 22.6% (intravenously) or 47.6 ± 25.5% (brain stem application). Results of this and previous studies indicate 1) forebrain circuitry rostral to the pons is not essential for TNS inhibition; and 2) opioid receptors in the brain stem have a critical role in TNS inhibition of overactive bladder reflexes but are not involved in inhibition of normal bladder reflexes. Copyright © 2015 the American Physiological Society.

Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat.

PubMed

Anselmi, L; Toti, L; Bove, C; Travagli, R A

2017-11-01

Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1 ) assess the gastric effects of brain stem DA application, 2 ) identify the DA receptor subtype, and, 3 ) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway. Copyright © 2017 the American Physiological Society.

Testing the hypothesis of neurodegeneracy in respiratory network function with a priori transected arterially perfused brain stem preparation of rat

PubMed Central

Jones, Sarah E.

2016-01-01

Degeneracy of respiratory network function would imply that anatomically discrete aspects of the brain stem are capable of producing respiratory rhythm. To test this theory we a priori transected brain stem preparations before reperfusion and reoxygenation at 4 rostrocaudal levels: 1.5 mm caudal to obex (n = 5), at obex (n = 5), and 1.5 (n = 7) and 3 mm (n = 6) rostral to obex. The respiratory activity of these preparations was assessed via recordings of phrenic and vagal nerves and lumbar spinal expiratory motor output. Preparations with a priori transection at level of the caudal brain stem did not produce stable rhythmic respiratory bursting, even when the arterial chemoreceptors were stimulated with sodium cyanide (NaCN). Reperfusion of brain stems that preserved the pre-Bötzinger complex (pre-BötC) showed spontaneous and sustained rhythmic respiratory bursting at low phrenic nerve activity (PNA) amplitude that occurred simultaneously in all respiratory motor outputs. We refer to this rhythm as the pre-BötC burstlet-type rhythm. Conserving circuitry up to the pontomedullary junction consistently produced robust high-amplitude PNA at lower burst rates, whereas sequential motor patterning across the respiratory motor outputs remained absent. Some of the rostrally transected preparations expressed both burstlet-type and regular PNA amplitude rhythms. Further analysis showed that the burstlet-type rhythm and high-amplitude PNA had 1:2 quantal relation, with burstlets appearing to trigger high-amplitude bursts. We conclude that no degenerate rhythmogenic circuits are located in the caudal medulla oblongata and confirm the pre-BötC as the primary rhythmogenic kernel. The absence of sequential motor patterning in a priori transected preparations suggests that pontine circuits govern respiratory pattern formation. PMID:26888109

Brain stem serotonin protects blood pressure in neonatal rats exposed to episodic anoxia.

PubMed

Yang, Hsiao T; Cummings, Kevin J

2013-12-01

In neonatal rodents, a loss of brain stem serotonin [5-hydroxytryptamine (5-HT)] in utero or at birth compromises anoxia-induced gasping and the recovery of heart rate (HR) and breathing with reoxygenation (i.e., autoresuscitation). How mean arterial pressure (MAP) is influenced after an acute loss of brain stem 5-HT content is unknown. We hypothesized that a loss of 5-HT for ∼1 day would compromise MAP during episodic anoxia. We injected 6-fluorotryptophan (20 mg/kg ip) into rat pups (postnatal days 9-10 or 11-13, n = 22 treated, 24 control), causing a ∼70% loss of brain stem 5-HT. Pups were exposed to a maximum of 15 anoxic episodes, separated by 5 min of room air to allow autoresuscitation. In younger pups, we measured breathing frequency and tidal volume using "head-out" plethysmography and HR from the electrocardiogram. In older pups, we used whole body plethysmography to detect gasping, while monitoring MAP. Gasp latency and the time required for respiratory, HR, and MAP recovery following each episode were determined. Despite normal gasp latency, breathing frequency and a larger tidal volume (P < 0.001), 5-HT-deficient pups survived one-half the number of episodes as controls (P < 0.001). The anoxia-induced decrease in MAP experienced by 5-HT-deficient pups was double that of controls (P = 0.017), despite the same drop in HR (P = 0.48). MAP recovery was delayed ∼10 s by 5-HT deficiency (P = 0.001). Our data suggest a loss of brain stem 5-HT leads to a pronounced, premature loss of MAP in response to episodic anoxia. These data may help explain why some sudden infant death syndrome cases die from what appears to be cardiovascular collapse during apparent severe hypoxia.

Testing the hypothesis of neurodegeneracy in respiratory network function with a priori transected arterially perfused brain stem preparation of rat.

PubMed

Jones, Sarah E; Dutschmann, Mathias

2016-05-01

Degeneracy of respiratory network function would imply that anatomically discrete aspects of the brain stem are capable of producing respiratory rhythm. To test this theory we a priori transected brain stem preparations before reperfusion and reoxygenation at 4 rostrocaudal levels: 1.5 mm caudal to obex (n = 5), at obex (n = 5), and 1.5 (n = 7) and 3 mm (n = 6) rostral to obex. The respiratory activity of these preparations was assessed via recordings of phrenic and vagal nerves and lumbar spinal expiratory motor output. Preparations with a priori transection at level of the caudal brain stem did not produce stable rhythmic respiratory bursting, even when the arterial chemoreceptors were stimulated with sodium cyanide (NaCN). Reperfusion of brain stems that preserved the pre-Bötzinger complex (pre-BötC) showed spontaneous and sustained rhythmic respiratory bursting at low phrenic nerve activity (PNA) amplitude that occurred simultaneously in all respiratory motor outputs. We refer to this rhythm as the pre-BötC burstlet-type rhythm. Conserving circuitry up to the pontomedullary junction consistently produced robust high-amplitude PNA at lower burst rates, whereas sequential motor patterning across the respiratory motor outputs remained absent. Some of the rostrally transected preparations expressed both burstlet-type and regular PNA amplitude rhythms. Further analysis showed that the burstlet-type rhythm and high-amplitude PNA had 1:2 quantal relation, with burstlets appearing to trigger high-amplitude bursts. We conclude that no degenerate rhythmogenic circuits are located in the caudal medulla oblongata and confirm the pre-BötC as the primary rhythmogenic kernel. The absence of sequential motor patterning in a priori transected preparations suggests that pontine circuits govern respiratory pattern formation. Copyright © 2016 the American Physiological Society.

Stem cells distribution, cellular proliferation and migration in the adult Austrolebias charrua brain.

PubMed

Torres-Pérez, Maximiliano; Rosillo, Juan Carlos; Berrosteguieta, Ines; Olivera-Bravo, Silvia; Casanova, Gabriela; García-Verdugo, José Manuel; Fernández, Anabel Sonia

2017-10-15

Our previous studies demonstrated that Austrolebias charrua annual fish is an excellent model to study adult brain cell proliferation and neurogenesis due to the presence of active and fast neurogenesis in several regions during its short lifespan. Our main goal was to identify and localize the cells that compose the neurogenic areas throughout the Austrolebias brain. To do this, we used two thymidine halogenated analogs to detect cell proliferation at different survival times: 5-chloro-2'-deoxyuridine (CldU) at 1day and 5-iodo-2'-deoxyuridine (IdU) at 30days. Three types of proliferating cells were identified: I - transient amplifying or fast cycling cells that uptake CldU; II - stem cells or slow cycling cells, that were labeled with both CldU and IdU and did not migrate; and III - migrant cells that uptake IdU. Mapping and 3D-reconstruction of labeled nuclei showed that type I and type II cells were preferentially found close to ventricle walls. Type III cells appeared widespread and migrating in tangential and radial routes. Use of proliferation markers together with Vimentin or Nestin evidenced that type II cells are the putative stem cells that are located at the ventricular lumen. Double label cells with IdU+ and NeuN or HuC/D allowed us identify migrant neurons. Quantitation of labeled nuclei indicates that the proportion of putative stem cells is around 10% in all regions of the brain. This percentage of stem cells suggests the existence of a constant brain cell population in Austrolebias charrua that seems functional to the maintainance of adult neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Senescence from glioma stem cell differentiation promotes tumor growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ouchi, Rie; Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550; Okabe, Sachiko

Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such asmore » IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.« less

Effect of alpha-tocopherol, pyridoxine and dexpanthenol on the stress in crease of nonesterified fatty acids levels in the brain.

PubMed

Chmela, Z; Sklenovský, A; Dostálová, K; Rypka, M

1993-01-01

The supposed antistress effect of vitamins-alpha-tocopherol, pyridoxine and dexpanthenol (pantothenic acid precursor)--was followed on the model of nociceptive stress in laboratory rats. The decrease of the stress enhancement of nonesterified fatty acids (NEFA), estimated in the brain cortex, hypothalamus and the brain stem, was taken for the indicator of the antistress effect. Nonesterified fatty acids were determined with the help of gas chromatography following the separation performed by thin layer chromatographic method. Five-day application of alpha-tocopherol acetate (per os, 300 mg.kg-1) led to a decrease of the stress enhancement of arachidonic acid level in the brain stem.

Maternal Embryonic Leucine-zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

PubMed Central

Ganguly, Ranjit; Hong, Christopher; Smith, Luke; Kornblum, Harley I; Nakano, Ichiro

2014-01-01

Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of protein Serine/Threonine kinases that has recently gained significant attention in the stem cell and cancer biology field. Recent studies suggest that activation of this kinase is tightly associated with extended survival and accelerated proliferation of cancer stem cells (CSCs) in various organs. Overexpression of MELK has been noted in various cancers, including colon, breast, ovaries, pancreas, prostate, and brain, making the inhibition of MELK an attractive therapeutic strategy for a variety of cancers. In the experimental cancer models, depletion of MELK by RNA interference or small molecule inhibitors induces apoptotic cell death of cancer stem cells derived from glioblastoma and breast cancer, both in vitro and in vivo. Mechanism of action of MELK includes, yet may not be restricted to, direct binding and activation of the oncogenic transcription factors c-JUN and FOXM1 in cancer cells but not in the normal counterparts. Following these pre-clinical studies, the Phase I clinical trial for advanced cancers with OTS167 started in 2013, as the first-in-class MELK inhibitor. This review summarizes the current molecular understanding of MELK and the recent pre-clinical studies about MELK as a cancer therapeutic target. PMID:24795222

Simulation of proliferation and differentiation of cells in a stem-cell niche

NASA Astrophysics Data System (ADS)

Zhdanov, Vladimir P.

2008-10-01

Stem-cell niches represent microscopic compartments formed of environmental cells that nurture stem cells and enable them to maintain tissue homeostasis. The spatio-temporal kinetics of proliferation and differentiation of cells in such niches depend on the specifics of the niche structure and on adhesion and communication between cells and may also be influenced by spatial constraints on cell division. We propose a generic lattice model, taking all these factors into account, and systematically illustrate their role. The model is motivated by the experimental data available for the niches located in the subventricular zone of adult mammalian brain. The general conclusions drawn from our Monte Carlo simulations are applicable to other niches as well. One of our main findings is that the kinetics under consideration are highly stochastic due to a relatively small number of cells proliferating and differentiating in a niche and the autocatalytic character of the symmetric cell division. In particular, the kinetics exhibit huge stochastic bursts especially if the adhesion between cells is taken into account. In addition, the results obtained show that despite the small number of cells present in stem-cell niches, their arrangement can be predetermined to appreciable extent provided that the adhesion of different cells is different so that they tend to segregate.

MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling

PubMed Central

Zhao, Chunnian; Sun, GuoQiang; Li, Shengxiu; Lang, Ming-Fei; Yang, Su; Li, Wendong; Shi, Yanhong

2010-01-01

Neural stem cell self-renewal and differentiation is orchestrated by precise control of gene expression involving nuclear receptor TLX. Let-7b, a member of the let-7 microRNA family, is expressed in mammalian brains and exhibits increased expression during neural differentiation. However, the role of let-7b in neural stem cell proliferation and differentiation remains unknown. Here we show that let-7b regulates neural stem cell proliferation and differentiation by targeting the stem cell regulator TLX and the cell cycle regulator cyclin D1. Overexpression of let-7b led to reduced neural stem cell proliferation and increased neural differentiation, whereas antisense knockdown of let-7b resulted in enhanced proliferation of neural stem cells. Moreover, in utero electroporation of let-7b to embryonic mouse brains led to reduced cell cycle progression in neural stem cells. Introducing an expression vector of Tlx or cyclin D1 that lacks the let-7b recognition site rescued let-7b-induced proliferation deficiency, suggesting that both TLX and cyclin D1 are important targets for let-7b-mediated regulation of neural stem cell proliferation. Let-7b, by targeting TLX and cyclin D1, establishes an efficient strategy to control neural stem cell proliferation and differentiation. PMID:20133835

MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling.

PubMed

Zhao, Chunnian; Sun, GuoQiang; Li, Shengxiu; Lang, Ming-Fei; Yang, Su; Li, Wendong; Shi, Yanhong

2010-02-02

Neural stem cell self-renewal and differentiation is orchestrated by precise control of gene expression involving nuclear receptor TLX. Let-7b, a member of the let-7 microRNA family, is expressed in mammalian brains and exhibits increased expression during neural differentiation. However, the role of let-7b in neural stem cell proliferation and differentiation remains unknown. Here we show that let-7b regulates neural stem cell proliferation and differentiation by targeting the stem cell regulator TLX and the cell cycle regulator cyclin D1. Overexpression of let-7b led to reduced neural stem cell proliferation and increased neural differentiation, whereas antisense knockdown of let-7b resulted in enhanced proliferation of neural stem cells. Moreover, in utero electroporation of let-7b to embryonic mouse brains led to reduced cell cycle progression in neural stem cells. Introducing an expression vector of Tlx or cyclin D1 that lacks the let-7b recognition site rescued let-7b-induced proliferation deficiency, suggesting that both TLX and cyclin D1 are important targets for let-7b-mediated regulation of neural stem cell proliferation. Let-7b, by targeting TLX and cyclin D1, establishes an efficient strategy to control neural stem cell proliferation and differentiation.

Apparent diffusion coefficient mapping in medulloblastoma predicts non-infiltrative surgical planes.

PubMed

Marupudi, Neena I; Altinok, Deniz; Goncalves, Luis; Ham, Steven D; Sood, Sandeep

2016-11-01

An appropriate surgical approach for posterior fossa lesions is to start tumor removal from areas with a defined plane to where tumor is infiltrating the brainstem or peduncles. This surgical approach minimizes risk of damage to eloquent areas. Although magnetic resonance imaging (MRI) is the current standard preoperative imaging obtained for diagnosis and surgical planning of pediatric posterior fossa tumors, it offers limited information on the infiltrative planes between tumor and normal structures in patients with medulloblastomas. Because medulloblastomas demonstrate diffusion restriction on apparent diffusion coefficient map (ADC map) sequences, we investigated the role of ADC map in predicting infiltrative and non-infiltrative planes along the brain stem and/or cerebellar peduncles by medulloblastomas prior to surgery. Thirty-four pediatric patients with pathologically confirmed medulloblastomas underwent surgical resection at our facility from 2004 to 2012. An experienced pediatric neuroradiologist reviewed the brain MRIs/ADC map, assessing the planes between the tumor and cerebellar peduncles/brain stem. An independent evaluator documented surgical findings from operative reports for comparison to the radiographic findings. The radiographic findings were statistically compared to the documented intraoperative findings to determine predictive value of the test in identifying tumor infiltration of the brain stem cerebellar peduncles. Twenty-six patients had preoperative ADC mapping completed and thereby, met inclusion criteria. Mean age at time of surgery was 8.3 ± 4.6 years. Positive predictive value of ADC maps to predict tumor invasion of the brain stem and cerebellar peduncles ranged from 69 to 88 %; negative predictive values ranged from 70 to 89 %. Sensitivity approached 93 % while specificity approached 78 %. ADC maps are valuable in predicting the infiltrative and non-infiltrative planes along the tumor and brain stem interface in medulloblastomas. Inclusion and evaluation of ADC maps in preoperative evaluation can assist in surgical resection planning in patients with medulloblastoma.

Light up the "no-man's land" on the brain stem.

PubMed

Kawase, T

1995-12-01

The ventral surface of the brain stem is anatomically surrounded by the clivus anteriorly, brain stem posteriorly and by the petrous pyramid and cranial nerves from IIIrd to XIIth laterally in the deep posterior cranial fossa. Neurosurgical extra-axial pathologies arising from the area are aneurysms on the vertebro-basilar artery, benign tumors such as clival meningiomas, chordomas, chondromas, trigeminal neurinomas and prepontine epidermoid tumors. Surgical access to the area had been difficult for long years since the neurosurgery was established, because located deeply in such a surgical blindness, so-called "no-man's land". However, recent technical development of "skull base surgery" is opening new doors to light up the surgical darkness of the "no-man's land". This paper reviews the history, development, technique and future prospect of the skull base surgery to open the "no-man's land".

Development and aging of a brain neural stem cell niche.

PubMed

Conover, Joanne C; Todd, Krysti L

2017-08-01

In the anterior forebrain, along the lateral wall of the lateral ventricles, a neurogenic stem cell niche is found in a region referred to as the ventricular-subventricular zone (V-SVZ). In rodents, robust V-SVZ neurogenesis provides new neurons to the olfactory bulb throughout adulthood; however, with increasing age stem cell numbers are reduced and neurogenic capacity is significantly diminished, but new olfactory bulb neurons continue to be produced even in old age. Humans, in contrast, show little to no new neurogenesis after two years of age and whether V-SVZ neural stem cells persist in the adult human brain remains unclear. Here, we review functional and organizational differences in the V-SVZ stem cell niche of mice and humans, and examine how aging affects the V-SVZ niche and its associated functions. Copyright © 2016 Elsevier Inc. All rights reserved.

Gliomagenesis and neural stem cells: Key role of hypoxia and concept of tumor "neo-niche".

PubMed

Diabira, Sylma; Morandi, Xavier

2008-01-01

Gliomas represent the most common primary brain tumors and the most devastating pathology of the central nervous system. Despite progress in conventional treatments, the prognosis remains dismal. Recent studies have suggested that a glioma brain tumor may arise from a "cancer stem cell". To understand this theory we summarize studies of the concepts of neural stem cell, and its specialized microenvironment, namely the niche which can regulate balanced self-renewal, differentiation and stem cell quiescence. We summarize the molecular mechanism known or postulated to be involved in the disregulation of normal stem cells features allowing them to undergo neoplasic transformation. We seek data pointing out the key role of hypoxia in normal homeostasis of stem cells and in the initiation, development and aggressiveness of gliomas. We develop the concept of tumor special microenvironment and we propose the new concept of neo-niche, surrounding the glioma, in which hypoxia could be a key factor to recruit and deregulate different stem cells for gliogenesis process. Substantial advances in treatment would come from obtaining better knowledge of molecular impairs of this disease.

Consecutive light microscopy, scanning-transmission electron microscopy and transmission electron microscopy of traumatic human brain oedema and ischaemic brain damage.

PubMed

Castejon, O J; Castejon, H V; Diaz, M; Castellano, A

2001-10-01

Cortical biopsies of 11 patients with traumatic brain oedema were consecutively studied by light microscopy (LM) using thick plastic sections, scanning-transmission electron microscopy ((S)TEM) using semithin plastic sections and transmission electron microscopy (TEM) using ultrathin sections. Samples were glutaraldehyde-osmium fixed and embedded in Araldite or Epon. Thick sections were stained with toluidine-blue for light microscopy. Semithin sections were examined unstained and uncoated for (S)TEM. Ultrathin sections were stained with uranyl and lead. Perivascular haemorrhages and perivascular extravasation of proteinaceous oedema fluid were observed in both moderate and severe oedema. Ischaemic pyramidal and non-pyramidal nerve cells appeared shrunken, electron dense and with enlargement of intracytoplasmic membrane compartment. Notably swollen astrocytes were observed in all samples examined. Glycogen-rich and glycogen-depleted astrocytes were identified in anoxic-ischaemic regions. Dark and hydropic satellite, interfascicular and perivascular oligodendrocytes were also found. The status spongiosus of severely oedematous brain parenchyma observed by LM and (S)TEM was correlated with the enlarged extracellular space and disrupted neuropil observed by TEM. The (S)TEM is recommended as a suitable technique for studying pathological processes in the central nervous system and as an informative adjunct to LM and TEM.

Sensorimotor Functional and Structural Networks after Intracerebral Stem Cell Grafts in the Ischemic Mouse Brain.

PubMed

Green, Claudia; Minassian, Anuka; Vogel, Stefanie; Diedenhofen, Michael; Beyrau, Andreas; Wiedermann, Dirk; Hoehn, Mathias

2018-02-14

Past investigations on stem cell-mediated recovery after stroke have limited their focus on the extent and morphological development of the ischemic lesion itself over time or on the integration capacity of the stem cell graft ex vivo However, an assessment of the long-term functional and structural improvement in vivo is essential to reliably quantify the regenerative capacity of cell implantation after stroke. We induced ischemic stroke in nude mice and implanted human neural stem cells (H9 derived) into the ipsilateral cortex in the acute phase. Functional and structural connectivity changes of the sensorimotor network were noninvasively monitored using magnetic resonance imaging for 3 months after stem cell implantation. A sharp decrease of the functional sensorimotor network extended even to the contralateral hemisphere, persisting for the whole 12 weeks of observation. In mice with stem cell implantation, functional networks were stabilized early on, pointing to a paracrine effect as an early supportive mechanism of the graft. This stabilization required the persistent vitality of the stem cells, monitored by bioluminescence imaging. Thus, we also observed deterioration of the early network stabilization upon vitality loss of the graft after a few weeks. Structural connectivity analysis showed fiber-density increases between the cortex and white matter regions occurring predominantly on the ischemic hemisphere. These fiber-density changes were nearly the same for both study groups. This motivated us to hypothesize that the stem cells can influence, via early paracrine effect, the functional networks, while observed structural changes are mainly stimulated by the ischemic event. SIGNIFICANCE STATEMENT In recent years, research on strokes has made a shift away from a focus on immediate ischemic effects and towards an emphasis on the long-range effects of the lesion on the whole brain. Outcome improvements in stem cell therapies also require the understanding of their influence on the whole-brain networks. Here, we have longitudinally and noninvasively monitored the structural and functional network alterations in the mouse model of focal cerebral ischemia. Structural changes of fiber-density increases are stimulated in the endogenous tissue without further modulation by the stem cells, while functional networks are stabilized by the stem cells via a paracrine effect. These results will help decipher the underlying networks of brain plasticity in response to cerebral lesions and offer clues to unravelling the mystery of how stem cells mediate regeneration. Copyright © 2018 the authors 0270-6474/18/381648-14$15.00/0.

Go with the Flow: Cerebrospinal Fluid Flow Regulates Neural Stem Cell Proliferation.

PubMed

Kaneko, Naoko; Sawamoto, Kazunobu

2018-06-01

Adult neural stem cells in the wall of brain ventricles make direct contact with cerebrospinal fluid. In this issue of Cell Stem Cell, Petrik et al. (2018) demonstrate that these neural stem cells sense the flow of cerebrospinal fluid through a transmembrane sodium channel, ENaC, which regulates their proliferation. Copyright © 2018 Elsevier Inc. All rights reserved.

Medical diagnosis imaging systems: image and signal processing applications aided by fuzzy logic

NASA Astrophysics Data System (ADS)

Hata, Yutaka

2010-04-01

First, we describe an automated procedure for segmenting an MR image of a human brain based on fuzzy logic for diagnosing Alzheimer's disease. The intensity thresholds for segmenting the whole brain of a subject are automatically determined by finding the peaks of the intensity histogram. After these thresholds are evaluated in a region growing, the whole brain can be identified. Next, we describe a procedure for decomposing the obtained whole brain into the left and right cerebral hemispheres, the cerebellum and the brain stem. Our method then identified the whole brain, the left cerebral hemisphere, the right cerebral hemisphere, the cerebellum and the brain stem. Secondly, we describe a transskull sonography system that can visualize the shape of the skull and brain surface from any point to examine skull fracture and some brain diseases. We employ fuzzy signal processing to determine the skull and brain surface. The phantom model, the animal model with soft tissue, the animal model with brain tissue, and a human subjects' forehead is applied in our system. The all shapes of the skin surface, skull surface, skull bottom, and brain tissue surface are successfully determined.

A role for adult TLX-positive neural stem cells in learning and behaviour.

PubMed

Zhang, Chun-Li; Zou, Yuhua; He, Weimin; Gage, Fred H; Evans, Ronald M

2008-02-21

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

The Emerging Role of Epigenetics in Stroke

PubMed Central

Qureshi, Irfan A.; Mehler, Mark F.

2013-01-01

The transplantation of exogenous stem cells and the activation of endogenous neural stem and progenitor cells (NSPCs) are promising treatments for stroke. These cells can modulate intrinsic responses to ischemic injury and may even integrate directly into damaged neural networks. However, the neuroprotective and neural regenerative effects that can be mediated by these cells are limited and may even be deleterious. Epigenetic reprogramming represents a novel strategy for enhancing the intrinsic potential of the brain to protect and repair itself by modulating pathologic neural gene expression and promoting the recapitulation of seminal neural developmental processes. In fact, recent evidence suggests that emerging epigenetic mechanisms are critical for orchestrating nearly every aspect of neural development and homeostasis, including brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, neural subtype specification, and synaptic and neural network connectivity and plasticity. In this review, we survey the therapeutic potential of exogenous stem cells and endogenous NSPCs and highlight innovative technological approaches for designing, developing, and delivering epigenetic therapies for targeted reprogramming of endogenous pools of NSPCs, neural cells at risk, and dysfunctional neural networks to rescue and restore neurologic function in the ischemic brain. PMID:21403016

SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions.

PubMed

Akiguchi, Ichiro; Pallàs, Mercè; Budka, Herbert; Akiyama, Haruhiko; Ueno, Masaki; Han, Jingxian; Yagi, Hideo; Nishikawa, Tomohumi; Chiba, Yoichi; Sugiyama, Hiroshi; Takahashi, Ryoya; Unno, Keiko; Higuchi, Keiichi; Hosokawa, Masanori

2017-08-01

Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders. © 2017 Japanese Society of Neuropathology.

Wiring Pathways to Replace Aggression

ERIC Educational Resources Information Center

Bath, Howard

2006-01-01

The previous article in this series introduced the triune brain, the three components of which handle specialized life tasks. The survival brain, or brain stem, directs automatic physiological functions, such as heartbeat and breathing, and mobilizes fight/flight behaviour in times of threat. The emotional (or limbic) brain activates positive or…

Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury

PubMed Central

Zhou, Hai-xiao; Liu, Zhi-gang; Liu, Xiao-jiao; Chen, Qian-xue

2016-01-01

Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5–3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions. PMID:26981097

Cell fusion in the brain: two cells forward, one cell back.

PubMed

Kemp, Kevin; Wilkins, Alastair; Scolding, Neil

2014-11-01

Adult stem cell populations, notably those which reside in the bone marrow, have been shown to contribute to several neuronal cell types in the rodent and human brain. The observation that circulating bone marrow cells can migrate into the central nervous system and fuse with, in particular, cerebellar Purkinje cells has suggested, at least in part, a potential mechanism behind this process. Experimentally, the incidence of cell fusion in the brain is enhanced with age, radiation exposure, inflammation, chemotherapeutic drugs and even selective damage to the neurons themselves. The presence of cell fusion, shown by detection of increased bi-nucleated neurons, has also been described in a variety of human central nervous system diseases, including both multiple sclerosis and Alzheimer's disease. Accumulating evidence is therefore raising new questions into the biological significance of cell fusion, with the possibility that it represents an important means of cell-mediated neuroprotection or rescue of highly complex neurons that cannot be replaced in adult life. Here, we discuss the evidence behind this phenomenon in the rodent and human brain, with a focus on the subsequent research investigating the physiological mechanisms of cell fusion underlying this process. We also highlight how these studies offer new insights into endogenous neuronal repair, opening new exciting avenues for potential therapeutic interventions against neurodegeneration and brain injury.

Knowledge and attitudes of nurses on a regional neurological intensive therapy unit towards brain stem death and organ donation.

PubMed

Davies, C

1997-01-01

The study aimed to explore nurses knowledge and attitudes towards brain stem death and organ donation. An ex post facto research design was used to determine relationships between variables. A 16 item questionnaire was used to collect data. Statistical analysis revealed one significant result. The limitations of the sample size is acknowledged and the conclusion suggests a larger study is required.

Novel Regenerative Therapies Based on Regionally Induced Multipotent Stem Cells in Post-Stroke Brains: Their Origin, Characterization, and Perspective.

PubMed

Takagi, Toshinori; Yoshimura, Shinichi; Sakuma, Rika; Nakano-Doi, Akiko; Matsuyama, Tomohiro; Nakagomi, Takayuki

2017-12-01

Brain injuries such as ischemic stroke cause severe neural loss. Until recently, it was believed that post-ischemic areas mainly contain necrotic tissue and inflammatory cells. However, using a mouse model of cerebral infarction, we demonstrated that stem cells develop within ischemic areas. Ischemia-induced stem cells can function as neural progenitors; thus, we initially named them injury/ischemia-induced neural stem/progenitor cells (iNSPCs). However, because they differentiate into more than neural lineages, we now refer to them as ischemia-induced multipotent stem cells (iSCs). Very recently, we showed that putative iNSPCs/iSCs are present within post-stroke areas in human brains. Because iNSPCs/iSCs isolated from mouse and human ischemic tissues can differentiate into neuronal lineages in vitro, it is possible that a clearer understanding of iNSPC/iSC profiles and the molecules that regulate iNSPC/iSC fate (e.g., proliferation, differentiation, and survival) would make it possible to perform neural regeneration/repair in patients following stroke. In this article, we introduce the origin and traits of iNSPCs/iSCs based on our reports and recent viewpoints. We also discuss their possible contribution to neurogenesis through endogenous and exogenous iNSPC/iSC therapies following ischemic stroke.

Neuronal sources of hedgehog modulate neurogenesis in the adult planarian brain.

PubMed

Currie, Ko W; Molinaro, Alyssa M; Pearson, Bret J

2016-11-19

The asexual freshwater planarian is a constitutive adult, whose central nervous system (CNS) is in a state of constant homeostatic neurogenesis. However, very little is known about the extrinsic signals that act on planarian stem cells to modulate rates of neurogenesis. We have identified two planarian homeobox transcription factors, Smed-nkx2.1 and Smed-arx , which are required for the maintenance of cholinergic, GABAergic, and octopaminergic neurons in the planarian CNS. These very same neurons also produce the planarian hedgehog ligand ( Smed-hh ), which appears to communicate with brain-adjacent stem cells to promote normal levels of neurogenesis. Planarian stem cells nearby the brain express core hh signal transduction genes, and consistent hh signaling levels are required to maintain normal production of neural progenitor cells and new mature cholinergic neurons, revealing an important mitogenic role for the planarian hh signaling molecule in the adult CNS.

A Case of Myxedema Coma Presenting as a Brain Stem Infarct in a 74-Year-Old Korean Woman

PubMed Central

Ahn, Ji Yun; Kwon, Hyuk-Sool; Ahn, Hee Chol

2010-01-01

Myxedema coma is the extreme form of untreated hypothyroidism. In reality, few patients present comatose with severe myxedema. We describe a patient with myxedema coma which was initially misdiagnosed as a brain stem infarct. She presented to the hospital with alteration of the mental status, generalized edema, hypothermia, hypoventilation, and hypotension. Initially her brain stem reflexes were absent. After respiratory and circulatory support, her neurologic status was not improved soon. The diagnosis of myxedema coma was often missed or delayed due to various clinical findings and concomitant medical condition and precipitating factors. It is more difficult to diagnose when a patient has no medical history of hypothyroidism. A high index of clinical suspicion can make a timely diagnosis and initiate appropriate treatment. We report this case to alert clinicians considering diagnosis of myxedema coma in patients with severe decompensated metabolic state including mental change. PMID:20808690

A case of myxedema coma presenting as a brain stem infarct in a 74-year-old Korean woman.

PubMed

Ahn, Ji Yun; Kwon, Hyuk-Sool; Ahn, Hee Chol; Sohn, You Dong

2010-09-01

Myxedema coma is the extreme form of untreated hypothyroidism. In reality, few patients present comatose with severe myxedema. We describe a patient with myxedema coma which was initially misdiagnosed as a brain stem infarct. She presented to the hospital with alteration of the mental status, generalized edema, hypothermia, hypoventilation, and hypotension. Initially her brain stem reflexes were absent. After respiratory and circulatory support, her neurologic status was not improved soon. The diagnosis of myxedema coma was often missed or delayed due to various clinical findings and concomitant medical condition and precipitating factors. It is more difficult to diagnose when a patient has no medical history of hypothyroidism. A high index of clinical suspicion can make a timely diagnosis and initiate appropriate treatment. We report this case to alert clinicians considering diagnosis of myxedema coma in patients with severe decompensated metabolic state including mental change.

Chronic inflammation and impaired development of the preterm brain.

PubMed

Bennet, Laura; Dhillon, Simerdeep; Lear, Chris A; van den Heuij, Lotte; King, Victoria; Dean, Justin M; Wassink, Guido; Davidson, Joanne O; Gunn, Alistair Jan

2018-02-01

The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair. Copyright © 2017 Elsevier B.V. All rights reserved.

Proton Beam Radiation Therapy in Treating Patients With Low Grade Gliomas

ClinicalTrials.gov

2015-12-14

Adult Brain Tumor; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Melanocytic Lesion; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma; Adult Pineocytoma; Recurrent Adult Brain Tumor

[Clinical-neuropsychological study of patients with hematomas, cavernomas and arteriovenous malformations of the brain stem].

PubMed

Buklina, S B; Gavriushin, A V; Okishev, D N

2009-01-01

A clinical-neuropsychological study of 25 patients with hematomas, cavernomas and arteriovenous malformations of different brain stem regions has been performed. Patients with hydrocephalic-hypertensive and dislocation syndromes as well as a history of neurological diseases were excluded from the study. All patients had hemorrhages in different brain stem regions, most of which had occurred several weeks ago. Hematomas were located in different regions of the pons (14 patients) and midbrain (7 patients) and spread to both regions in 4 patients. All patients underwent MRI study of the brain and complex neuropsychological investigation using the A.R. Luria's method. Neuropsychological symptoms before the surgery were found in 20 patients. Cognitive disturbances similar by the lesion of frontal lobes, in particular the promoter zone, that manifested themselves in disturbances of dynamic praxis, writing, verbal memory, were observed most often. Cognitive disturbances similar by the lesion of occipital hemisphere regions, i.e. disturbances of visual gnosis and spatial defects, were found less often. The most severe symptoms were observed in the lesion of the midbrain and upper regions of the pons.

Astrocyte-Secreted Factors Selectively Alter Neural Stem and Progenitor Cell Proliferation in the Fragile X Mouse

PubMed Central

Sourial, Mary; Doering, Laurie C.

2016-01-01

An increasing body of evidence indicates that astrocytes contribute to the governance and fine tuning of stem and progenitor cell production during brain development. The effect of astrocyte function in cell production in neurodevelopmental disorders is unknown. We used the Neural Colony Forming Cell assay to determine the effect of astrocyte conditioned media (ACM) on the generation of neurospheres originating from either progenitor cells or functional stem cells in the knock out (KO) Fragile X mouse model. ACM from both normal and Fmr1-KO mice generated higher percentages of smaller neurospheres indicative of restricted proliferation of the progenitor cell population in Fmr1-KO brains. Wild type (WT) neurospheres, but not KO neurospheres, showed enhanced responses to ACM from the Fmr1-KO mice. In particular, Fmr1-KO ACM increased the percentage of large neurospheres generated, representative of spheres produced from neural stem cells. We also used 2D DIGE to initiate identification of the astrocyte-secreted proteins with differential expression between Fmr1-KO and WT cortices and hippocampi. The results further support the critical role of astrocytes in governing neural cell production in brain development and point to significant alterations in neural cell proliferation due to astrocyte secreted factors from the Fragile X brain. Highlights: • We studied the proliferation of neural stem and progenitor cells in Fragile X. • We examined the role of astrocyte-secreted factors in neural precursor cell biology. • Astrocyte-secreted factors with differential expression in Fragile X identified. PMID:27242437

Genetic deletion of Rnd3 in neural stem cells promotes proliferation via upregulation of Notch signaling.

PubMed

Dong, Huimin; Lin, Xi; Li, Yuntao; Hu, Ronghua; Xu, Yang; Guo, Xiaojie; La, Qiong; Wang, Shun; Fang, Congcong; Guo, Junli; Li, Qi; Mao, Shanping; Liu, Baohui

2017-10-31

Rnd3, a Rho GTPase, is involved in the inhibition of actin cytoskeleton dynamics through the Rho kinase-dependent signaling pathway. We previously demonstrated that mice with genetic deletion of Rnd3 developed a markedly larger brain compared with wild-type mice. Here, we demonstrate that Rnd3 knockout mice developed an enlarged subventricular zone, and we identify a novel role for Rnd3 as an inhibitor of Notch signaling in neural stem cells. Rnd3 deficiency, both in vivo and in vitro , resulted in increased levels of Notch intracellular domain protein. This led to enhanced Notch signaling and promotion of aberrant neural stem cell growth, thereby resulting in a larger subventricular zone and a markedly larger brain. Inhibition of Notch activity abrogated this aberrant neural stem cell growth.

STEM Tones Pre-Activate Suffixes in the Brain

ERIC Educational Resources Information Center

Söderström, Pelle; Horne, Merle; Roll, Mikael

2017-01-01

Results from the present event-related potentials (ERP) study show that tones on Swedish word stems can rapidly pre-activate upcoming suffixes, even when the word stem does not carry any lexical meaning. Results also show that listeners are able to rapidly restore suffixes which are replaced with a cough. Accuracy in restoring suffixes correlated…

A PITX3-EGFP Reporter Line Reveals Connectivity of Dopamine and Non-dopamine Neuronal Subtypes in Grafts Generated from Human Embryonic Stem Cells.

PubMed

Niclis, Jonathan C; Gantner, Carlos W; Hunt, Cameron P J; Kauhausen, Jessica A; Durnall, Jennifer C; Haynes, John M; Pouton, Colin W; Parish, Clare L; Thompson, Lachlan H

2017-09-12

Development of safe and effective stem cell-based therapies for brain repair requires an in-depth understanding of the in vivo properties of neural grafts generated from human stem cells. Replacing dopamine neurons in Parkinson's disease remains one of the most anticipated applications. Here, we have used a human PITX3-EGFP embryonic stem cell line to characterize the connectivity of stem cell-derived midbrain dopamine neurons in the dopamine-depleted host brain with an unprecedented level of specificity. The results show that the major A9 and A10 subclasses of implanted dopamine neurons innervate multiple, developmentally appropriate host targets but also that the majority of graft-derived connectivity is non-dopaminergic. These findings highlight the promise of stem cell-based procedures for anatomically correct reconstruction of specific neuronal pathways but also emphasize the scope for further refinement in order to limit the inclusion of uncharacterized and potentially unwanted cell types. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The number of stem cells in the subependymal zone of the adult rodent brain is correlated with the number of ependymal cells and not with the volume of the niche.

PubMed

Kazanis, Ilias; Ffrench-Constant, Charles

2012-05-01

The mammalian subependymal zone (SEZ; often called subventricular) situated at the lateral walls of the lateral ventricles of the brain contains a pool of relatively quiescent adult neural stem cells whose neurogenic activity persists throughout life. These stem cells are positioned in close proximity both to the ependymal cells that provide the cerebrospinal fluid interface and to the blood vessel endothelial cells, but the relative contribution of these 2 cell types to stem cell regulation remains undetermined. Here, we address this question by analyzing a naturally occurring example of volumetric scaling of the SEZ in a comparison of the mouse SEZ with the larger rat SEZ. Our analysis reveals that the number of stem cells in the SEZ niche is correlated with the number of ependymal cells rather than with the volume, thereby indicating the importance of ependymal-derived factors in the formation and function of the SEZ. The elucidation of the factors generated by ependymal cells that regulate stem cell numbers within the SEZ is, therefore, of importance for stem cell biology and regenerative neuroscience.

Adult human neural stem cell therapeutics: Current developmental status and prospect.

PubMed

Nam, Hyun; Lee, Kee-Hang; Nam, Do-Hyun; Joo, Kyeung Min

2015-01-26

Over the past two decades, regenerative therapies using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings. In this review, we discuss the scientific and clinical basics of adult neural stem cells (aNSCs), and their current developmental status as cell therapeutics for neurological disease. Compared with other types of stem cells, aNSCs have clinical advantages, such as limited proliferation, inborn differentiation potential into functional neural cells, and no ethical issues. In spite of the merits of aNSCs, difficulties in the isolation from the normal brain, and in the in vitro expansion, have blocked preclinical and clinical study using aNSCs. However, several groups have recently developed novel techniques to isolate and expand aNSCs from normal adult brains, and showed successful applications of aNSCs to neurological diseases. With new technologies for aNSCs and their clinical strengths, previous hurdles in stem cell therapies for neurological diseases could be overcome, to realize clinically efficacious regenerative stem cell therapeutics.

Syringe needle skull penetration reduces brain injuries and secondary inflammation following intracerebral neural stem cell transplantation.

PubMed

Gao, Mou; Dong, Qin; Zhang, Hongtian; Yang, Yang; Zhu, Jianwei; Yang, Zhijun; Xu, Minhui; Xu, Ruxiang

2017-03-01

Intracerebral neural stem cell (NSC) transplantation is beneficial for delivering stem cell grafts effectively, however, this approach may subsequently result in brain injury and secondary inflammation. To reduce the risk of promoting brain injury and secondary inflammation, two methods were compared in the present study. Murine skulls were penetrated using a drill on the left side and a syringe needle on the right. Mice were randomly divided into three groups (n=84/group): Group A, receiving NSCs in the left hemisphere and PBS in the right; group B, receiving NSCs in the right hemisphere and PBS in the left; and group C, receiving equal NSCs in both hemispheres. Murine brains were stained for morphological analysis and subsequent evaluation of infiltrated immune cells. ELISA was performed to detect neurotrophic and immunomodulatory factors in the brain. The findings indicated that brain injury and secondary inflammation in the left hemisphere were more severe than those in the right hemisphere, following NSC transplantation. In contrast to the left hemisphere, more neurotrophic factors but less pro-inflammatory cytokines were detected in the right hemisphere. In addition, increased levels of neurotrophic factors and interleukin (IL)-10 were observed in the NSC transplantation side when compared with the PBS-treated hemispheres, although lower levels of IL-6 and tumor necrosis factor-α were detected. In conclusion, the present study indicated that syringe needle skull penetration vs. drill penetration is an improved method that reduces the risk of brain injury and secondary inflammation following intracerebral NSC transplantation. Furthermore, NSCs have the potential to modulate inflammation secondary to brain injuries.

A Brain Unfixed: Unlimited Neurogenesis and Regeneration of the Adult Planarian Nervous System

PubMed Central

Brown, David D. R.; Pearson, Bret J.

2017-01-01

Powerful genetic tools in classical laboratory models have been fundamental to our understanding of how stem cells give rise to complex neural tissues during embryonic development. In contrast, adult neurogenesis in our model systems, if present, is typically constrained to one or a few zones of the adult brain to produce a limited subset of neurons leading to the dogma that the brain is primarily fixed post-development. The freshwater planarian (flatworm) is an invertebrate model system that challenges this dogma. The planarian possesses a brain containing several thousand neurons with very high rates of cell turnover (homeostasis), which can also be fully regenerated de novo from injury in just 7 days. Both homeostasis and regeneration depend on the activity of a large population of adult stem cells, called neoblasts, throughout the planarian body. Thus, much effort has been put forth to understand how the flatworm can continually give rise to the diversity of cell types found in the adult brain. Here we focus on work using single-cell genomics and functional analyses to unravel the cellular hierarchies from stem cell to neuron. In addition, we will review what is known about how planarians utilize developmental signaling to maintain proper tissue patterning, homeostasis, and cell-type diversity in their brains. Together, planarians are a powerful emerging model system to study the dynamics of adult neurogenesis and regeneration. PMID:28588444

Control of adult neurogenesis by programmed cell death in the mammalian brain.

PubMed

Ryu, Jae Ryun; Hong, Caroline Jeeyeon; Kim, Joo Yeon; Kim, Eun-Kyoung; Sun, Woong; Yu, Seong-Woon

2016-04-21

The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

Bioreactivity: Studies on a Simple Brain Stem Reflex in Behaving Animals

DTIC Science & Technology

1990-08-10

problem in attempting to understand complex physiological processes, such as brain neuromodulation , or complex behavioral processes, such as arousal...containing only one synapse in brain, and receives dense inputs from two neurochemical systems important in neuromodulation and arousal. Initial

Bioreactivity: Studies on a Simple Brain Stem Reflex in Behaving Animals

DTIC Science & Technology

1990-01-04

attempting to understand complex physiological processes, such as brain neuromodulation , or complex behavioral processes, such as arousal, is finding a...one synapse in brain, and receives dense inputs from two neurochemical systems important in neuromodulation and arousal. Initial pharmacologic studies

Brain stem/brain stem occipital bone ratio and the four-line view in nuchal translucency images of fetuses with open spina bifida.

PubMed

Iuculano, Ambra; Zoppi, Maria Angelica; Piras, Alessandra; Arras, Maurizio; Monni, Giovanni

2014-09-10

Abstract Objective: Brain stem depth/brain stem occipital bone distance (BS/BSOB ratio) and the four-line view, in images obtained for nuchal translucency (NT) screening in fetuses with open spina bifida (OSB). Methods: Single center, retrospective study based on the assessment of NT screening images of fetuses with OSB. A ratio between the BS depth and the BSOB distance was calculated (BS/BSOB ratio) and the four-line view observed, and the sensitivity for a BS/BSOB ratio superior/equal to 1, and for the lack of detection of the four-line view were calculated. Results: There were 17 cases of prenatal diagnosis OSB. In six cases, the suspicion on OSB was raised during NT screening, in six cases, the diagnosis was made before 20 weeks and in five cases during anomaly scan. The BS/BSOB ratio was superior/equal to 1 in all 17 cases, and three lines, were visualized in 15/17 images of the OSB cases, being the sensitivity 100% (95% CI, 81 to 100%) and 88% (95% CI, 65 to 96%). Conclusion: Assessment of BS/BSOB ratio and four-line view in NT images is feasible detecting affected by OSB with high sensitivity. The presence of associated anomalies or of an enlarged NT enhances the early detection.

Brain stem venous congestion due to dural arteriovenous fistulas of the cavernous sinus.

PubMed

Kai, Y; Hamada, J I; Morioka, M; Yano, S; Ushio, Y

2004-10-01

Venous congestion of the brain stem due to dural arteriovenous fistulas (DAVFs) in the cavernous sinus is rare and presents therapeutic challenges. To assess the prognosis of patients with symptomatic DAVFs and brain stem dysfunction, we evaluated the degree of venous ischemia by examining pre- and post-treatment magnetic resonance images (MRI) in 2 patients presenting with venous congestion of the brain stem. A 56-year-old woman with left hemiparesis and a 70-year-old woman with gait disturbance attributable to right cavernous sinus DAVFs were referred to our hospital. In both cases, T2-weighted magnetic resonance imaging (MRI) disclosed a hyperintensity lesion in the brainstem due to venous congestion. Both patients underwent open surgery for direct embolization of the cavernous sinus because there were no approach routes for transvenous embolization. The patient whose pretreatment MRI demonstrated Gd enhancement continued to manifest neurological deficits and persistence of the abnormal hyperintensity on post-treatment T2-weighted MRI. In the other patient whose pretreatment MRI showed no Gd enhancement, treatment produced a complete response of her neurological deficit and disappearance of the abnormal hyperintensity area. We tentatively conclude that lesions corresponding to hyperintensity areas on non-Gd-enhanced, T2-weighted MRI may reflect a reversible condition whereas lesions identified as hyperintense areas on GD-enhanced T2-weighted MRI may be indicative of irreversibility.

Signaling mechanisms regulating adult neural stem cells and neurogenesis

PubMed Central

Faigle, Roland; Song, Hongjun

2012-01-01

Background Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain. Scope of review Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity. Major conclusions Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies. General significance A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. PMID:22982587

Myoclonus

MedlinePlus

... injury, stroke, brain tumors, kidney or liver failure, lipid storage disease, chemical or drug poisoning, or other ... example, is in the brain stem close to structures that are responsible for the startle response, an ...

Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation

PubMed Central

St. John, James A.; Walkden, Heidi; Nazareth, Lynn; Beagley, Kenneth W.; Batzloff, Michael R.

2016-01-01

Infection with Burkholderia pseudomallei causes melioidosis, a disease with a high mortality rate (20% in Australia and 40% in Southeast Asia). Neurological melioidosis is particularly prevalent in northern Australian patients and involves brain stem infection, which can progress to the spinal cord; however, the route by which the bacteria invade the central nervous system (CNS) is unknown. We have previously demonstrated that B. pseudomallei can infect the olfactory and trigeminal nerves within the nasal cavity following intranasal inoculation. As the trigeminal nerve projects into the brain stem, we investigated whether the bacteria could continue along this nerve to penetrate the CNS. After intranasal inoculation of mice, B. pseudomallei caused low-level localized infection within the nasal cavity epithelium, prior to invasion of the trigeminal nerve in small numbers. B. pseudomallei rapidly invaded the trigeminal nerve and crossed the astrocytic barrier to enter the brain stem within 24 h and then rapidly progressed over 2,000 μm into the spinal cord. To rule out that the bacteria used a hematogenous route, we used a capsule-deficient mutant of B. pseudomallei that does not survive in the blood and found that it also entered the CNS via the trigeminal nerve. This suggests that the primary route of entry is via the nerves that innervate the nasal cavity. We found that actin-mediated motility could facilitate initial infection of the olfactory epithelium. Thus, we have demonstrated that B. pseudomallei can rapidly infect the brain and spinal cord via the trigeminal nerve branches that innervate the nasal cavity. PMID:27382023

Involvement of PI3K and ROCK signaling pathways in migration of bone marrow-derived mesenchymal stem cells through human brain microvascular endothelial cell monolayers.

PubMed

Lin, Mei-Na; Shang, De-Shu; Sun, Wei; Li, Bo; Xu, Xin; Fang, Wen-Gang; Zhao, Wei-Dong; Cao, Liu; Chen, Yu-Hua

2013-06-04

Bone marrow-derived mesenchymal stem cells (MSC) represent an important and easily available source of stem cells for potential therapeutic use in neurological diseases. The entry of circulating cells into the central nervous system by intravenous administration requires, firstly, the passage of the cells across the blood-brain barrier (BBB). However, little is known of the details of MSC transmigration across the BBB. In the present study, we employed an in vitro BBB model constructed using a human brain microvascular endothelial cell monolayer to study the mechanism underlying MSC transendothelial migration. Transmigration assays, transendothelial electrical resistance (TEER) and horseradish peroxidase (HRP) flux assays showed that MSC could transmigrate through human brain microvascular endothelial cell monolayers by a paracellular pathway. Cell fractionation and immunofluorescence assays confirmed the disruption of tight junctions. Inhibition assays showed that a Rho-kinase (ROCK) inhibitor (Y27632) effectively promoted MSC transendothelial migration; conversely, a PI3K inhibitor (LY294002) blocked MSC transendothelial migration. Interestingly, adenovirus-mediated interference with ROCK in MSC significantly increased MSC transendothelial migration, and overexpression of a PI3K dominant negative mutant in MSC cells could block transendothelial migration. Our findings provide clear evidence that the PI3K and ROCK pathways are involved in MSC migration through human brain microvascular endothelial cell monolayers. The information yielded by this study may be helpful in constructing gene-modified mesenchymal stem cells that are able to penetrate the BBB effectively for cell therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Differentiation and characteristics of the enhanced green fluorescent protein gene transgenic goat neural stem cells cultured in attached and non-attached plates.

PubMed

Zheng, Yue-Mao; Dang, Yong-Hui; Qiu, Shuang; Qi, Ying-Pei; Xu, Yong-Ping; Sai, Wu-Jia-Fu

2011-08-01

The aims of this study were (i) to determine whether NSCs (neural stem cells) could be isolated from the brain of embryonic day 98 fetal goat, (ii) to determine if these stem cells have the capability of multipotent differentiation following transfection with a reporter gene, EGFP (enhanced green fluorescent protein) and (iii) to study the characteristics of the stem cells cultured in attached and non-attached plates. NSCs were isolated from embryonic day 98 fetal goat brain, transfected with EGFP gene using lipofection, and subcultured in attached and non-attached plates respectively. The transgenic stem cells were induced to differentiate into osteogenic and endothelial cells in vitro respectively. Markers associated with undifferentiated NSCs and their differentiated cells were tested by RT-PCR (reverse transcription-PCR). The results demonstrated that stem cells could be isolated from embryonic day 98 fetal goat brain, and EGFP gene could be transfected into the cells. The transgenic NSCs were capable of self-renewal, a defining property of stem cells, and were grown as free-floating neurospheres in non-attached plates. When the neurospheres were transferred and cultured in attached plates, cells migrate from the neurospheres and are grown as spindle cells. The stem cells were grown as quasi-circular cells when the single stem cells were cultured in attached plates. Both the NSCs cultured in non-attached and attached plates could express Hes1 (hairy and enhancer of split 1), Oct4 (octamer-binding protein 4), Nanog, Sox2 [SRY (sex-determining region Y)-box 2] and Nestin, while following differentiation cells expressed markers for osteogenic cells (Osteocalcin+ and Osteonectin+) and endothelium (CD34+ and eNOS+). The results demonstrated that the goat EGFP gene transgenic NSCs have the capability of multipotent differentiation, which means that the transgenic NSCs may be useful in cell transplantation studies in future.

Magnetic Enhancement of Stem Cell-Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood-Brain Barrier.

PubMed

Shen, Wei-Bin; Anastasiadis, Pavlos; Nguyen, Ben; Yarnell, Deborah; Yarowsky, Paul J; Frenkel, Victor; Fishman, Paul S

2017-07-01

Focused ultrasound (FUS)-mediated blood-brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls' Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles-loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection.

Symmetrical Curvilinear Cytotoxic Edema Along the Surface of the Brain Stem: A Probable New Magnetic Resonance Imaging Finding of Leptomeningeal Carcinomatosis.

PubMed

Khil, Eun Kyung; Lee, A Leum; Chang, Kee-Hyun; Yun, Tae Jin; Hong, Hyun Sook

2015-07-01

Lung cancer is one of the most common neoplasms to appear leptomeningeal metastasis (LM). Contrast-enhanced magnetic resonance imaging (MRI) is better diagnostic choice for LM and usually shows focal nodular or diffuse linear enhancement on the leptomeninges along the sulci and tentorium in the brain. We experienced atypical 2 cases of lung cancer in patients who showed unusual brain MRI finding of symmetrical curvilinear or band-like, nonenhancing cytotoxic edema along the surface of the brain stem. This finding is unique and different from the general findings of leptomeningeal metastasis. This unique imaging finding of symmetric curvilinear nonenhancing cytotoxic edema along the brainstem is extremely rare and represents a new presentation of leptomeningeal carcinomatosis.

Three-dimensional shape optimization of a cemented hip stem and experimental validations.

PubMed

Higa, Masaru; Tanino, Hiromasa; Nishimura, Ikuya; Mitamura, Yoshinori; Matsuno, Takeo; Ito, Hiroshi

2015-03-01

This study proposes novel optimized stem geometry with low stress values in the cement using a finite element (FE) analysis combined with an optimization procedure and experimental measurements of cement stress in vitro. We first optimized an existing stem geometry using a three-dimensional FE analysis combined with a shape optimization technique. One of the most important factors in the cemented stem design is to reduce stress in the cement. Hence, in the optimization study, we minimized the largest tensile principal stress in the cement mantle under a physiological loading condition by changing the stem geometry. As the next step, the optimized stem and the existing stem were manufactured to validate the usefulness of the numerical models and the results of the optimization in vitro. In the experimental study, strain gauges were embedded in the cement mantle to measure the strain in the cement mantle adjacent to the stems. The overall trend of the experimental study was in good agreement with the results of the numerical study, and we were able to reduce the largest stress by more than 50% in both shape optimization and strain gauge measurements. Thus, we could validate the usefulness of the numerical models and the results of the optimization using the experimental models. The optimization employed in this study is a useful approach for developing new stem designs.

Stereotactic Radiosurgery in Treating Patients With Brain Tumors

ClinicalTrials.gov

2012-03-21

Adult Central Nervous System Germ Cell Tumor; Adult Malignant Meningioma; Adult Medulloblastoma; Adult Noninfiltrating Astrocytoma; Adult Oligodendroglioma; Adult Craniopharyngioma; Adult Meningioma; Brain Metastases; Adult Ependymoma; Adult Pineal Parenchymal Tumor; Adult Brain Stem Glioma; Adult Infiltrating Astrocytoma; Mixed Gliomas; Stage IV Peripheral Primitive Neuroectodermal Tumor

Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.

PubMed

Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa; Leng, Yan; Liao, Hsiao-Mei; Maric, Dragan; Chuang, De-Maw

2016-07-01

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells. Our results suggest that preconditioning stem cells with the mood stabilizers lithium and VPA before transplantation may serve as an effective strategy for enhancing the therapeutic efficacy of stem cell-based therapies. Copyright © 2016. Published by Elsevier Inc.

Disease and Stem Cell-Based Analysis of the 2014 ASNTR Meeting

PubMed Central

Eve, David J.

2015-01-01

A wide variety of subjects are presented at the annual American Society of Neural Therapy and Repair meeting every year, as typified by this summary of the 2014 meeting. Parkinson’s disease-related presentations were again the most popular topic, with traumatic brain injury, spinal cord injury, and stroke being close behind. Other disorders included Huntington’s disease, brain cancer, and bipolar disorders. Several studies were related to multiple diseases, and many studies attempted to reveal more about the disease process. The use of scaffolds, drugs, and gene therapy as disease models and/or potential therapies were also featured. An increasing proportion of presentations related to stem cells, with the study of multiple stem cell types being the most common. Induced pluripotent stem cells were increasingly popular, including two presentations each on a muscle-derived dedifferentiated cell type and cells derived from bipolar patients. Other stem cells, including neural stem cells, mesenchymal stem cells, umbilical cord blood cells, and embryonic stem cells, were featured. More than 55% of the stem cell studies involved transplantation, with human-derived cells being the most frequently transplanted, while rats were the most common recipient. Two human autologous studies for spinal cord injury and hypoxia-derived encephalopathy, while a further three allogenic studies for stroke and spinal cord injury, were also featured. This year’s meeting highlights the increasing promise of stem cells and other therapies for the treatment of neurodegenerative disorders. PMID:26858901

Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

ClinicalTrials.gov

2018-01-26

Glioblastoma Multiforme; Fibrillary Astrocytoma of Brain; Glioma of Brainstem; Anaplastic Astrocytoma; Pilomyxoid Astrocytoma; Mixed Oligodendroglioma-Astrocytoma; Brain Stem Glioma; Diffuse Intrinsic Pontine Glioma

Proliferation versus Differentiation: Redefining Retinoic Acid's Role.

PubMed

Mosher, Kira Irving; Schaffer, David V

2018-06-05

Retinoic acid is commonly used in culture to differentiate stem cells into neurons and has established neural differentiation functions in vivo in developing and adult organisms. In this issue of Stem Cell Reports, Mishra et al. (2018) broaden its role in stem cell functions, showing that retinoic acid is necessary for stem and progenitor cell proliferation in the adult brain. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies.

PubMed

Ngen, Ethel J; Wang, Lee; Gandhi, Nishant; Kato, Yoshinori; Armour, Michael; Zhu, Wenlian; Wong, John; Gabrielson, Kathleen L; Artemov, Dmitri

2016-06-01

Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.

Brain, Behavior, and Immunity: Biobehavioral influences on recovery following hematopoietic stem cell transplantation

Cancer.gov

Review of hematopoietic stem cell transplantation and its potential “window of opportunity” during which interventions targeting stress-related behavioral factors can influence the survival, health, and well-being of recipients.

Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis.

PubMed

Bardella, Chiara; Al-Dalahmah, Osama; Krell, Daniel; Brazauskas, Pijus; Al-Qahtani, Khalid; Tomkova, Marketa; Adam, Julie; Serres, Sébastien; Lockstone, Helen; Freeman-Mills, Luke; Pfeffer, Inga; Sibson, Nicola; Goldin, Robert; Schuster-Böeckler, Benjamin; Pollard, Patrick J; Soga, Tomoyoshi; McCullagh, James S; Schofield, Christopher J; Mulholland, Paul; Ansorge, Olaf; Kriaucionis, Skirmantas; Ratcliffe, Peter J; Szele, Francis G; Tomlinson, Ian

2016-10-10

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1 R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1 R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oka, Naoki; Soeda, Akio; Inagaki, Akihito

2007-08-31

There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massivemore » expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche.« less

Genetic strategies to investigate neuronal circuit properties using stem cell-derived neurons

PubMed Central

Garcia, Isabella; Kim, Cynthia; Arenkiel, Benjamin R.

2012-01-01

The mammalian brain is anatomically and functionally complex, and prone to diverse forms of injury and neuropathology. Scientists have long strived to develop cell replacement therapies to repair damaged and diseased nervous tissue. However, this goal has remained unrealized for various reasons, including nascent knowledge of neuronal development, the inability to track and manipulate transplanted cells within complex neuronal networks, and host graft rejection. Recent advances in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology, alongside novel genetic strategies to mark and manipulate stem cell-derived neurons, now provide unprecedented opportunities to investigate complex neuronal circuits in both healthy and diseased brains. Here, we review current technologies aimed at generating and manipulating neurons derived from ESCs and iPSCs toward investigation and manipulation of complex neuronal circuits, ultimately leading to the design and development of novel cell-based therapeutic approaches. PMID:23264761

Neural Stem Cells: Implications for the Conventional Radiotherapy of Central Nervous System Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barani, Igor J.; Benedict, Stanley H.; Lin, Peck-Sun

Advances in basic neuroscience related to neural stem cells and their malignant counterparts are challenging traditional models of central nervous system tumorigenesis and intrinsic brain repair. Neurogenesis persists into adulthood predominantly in two neurogenic centers: subventricular zone and subgranular zone. Subventricular zone is situated adjacent to lateral ventricles and subgranular zone is confined to the dentate gyrus of the hippocampus. Neural stem cells not only self-renew and differentiate along multiple lineages in these regions, but also contribute to intrinsic brain plasticity and repair. Ionizing radiation can depopulate these exquisitely sensitive regions directly or impair in situ neurogenesis by indirect, dose-dependentmore » and inflammation-mediated mechanisms, even at doses <2 Gy. This review discusses the fundamental neural stem cell concepts within the framework of cumulative clinical experience with the treatment of central nervous system malignancies using conventional radiotherapy.« less

Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner

PubMed Central

Krejciova, Zuzana; Alibhai, James; Zhao, Chen; Rzechorzek, Nina M.; Ullian, Erik M.; Manson, Jean

2017-01-01

Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype–dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery. PMID:29141869

A High-Content Small Molecule Screen Identifies Sensitivity of Glioblastoma Stem Cells to Inhibition of Polo-Like Kinase 1

PubMed Central

Danovi, Davide; Folarin, Amos; Gogolok, Sabine; Ender, Christine; Elbatsh, Ahmed M. O.; Engström, Pär G.; Stricker, Stefan H.; Gagrica, Sladjana; Georgian, Ana; Yu, Ding; U, Kin Pong; Harvey, Kevin J.; Ferretti, Patrizia; Paddison, Patrick J.; Preston, Jane E.; Abbott, N. Joan; Bertone, Paul; Smith, Austin; Pollard, Steven M.

2013-01-01

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF−/−, or p53−/−), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value. PMID:24204733

Mechanistic insight into neurotoxicity induced by developmental insults

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tamm, Christoffer; Ceccatelli, Sandra

Epidemiological and/or experimental studies have shown that unfavorable prenatal environmental factors, such as stress or exposure to certain neurotoxic environmental contaminants, may have adverse consequences for neurodevelopment. Alterations in neurogenesis can have harmful effects not only for the developing nervous system, but also for the adult brain where neurogenesis is believed to play a role in learning, memory, and even in depression. Many recent advances in the understanding of the complex process of nervous system development can be integrated into the field of neurotoxicology. In the past 15 years we have been using cultured neural stem or progenitor cells tomore » investigate the effects of neurotoxic stimuli on cell survival, proliferation and differentiation, with special focus on heritable effects. This is an overview of the work performed by our group in the attempt to elucidate the mechanisms of developmental neurotoxicity and possibly provide relevant information for the understanding of the etiopathogenesis of complex brain disorders. - Highlights: • The developing nervous system is highly sensitive to toxic insults. • Neural stem cells are relevant models for mechanistic studies as well as for identifying heritable effects due to epigenetic changes. • Depending on the dose, the outcome of exposure to neurotoxicants ranges from altered proliferation and differentiation to cell death. • The elucidation of neurotoxicity mechanisms is relevant for understanding the etiopathogenesis of developmental and adult nervous system disorders.« less

Magnetoencephalographic accuracy profiles for the detection of auditory pathway sources.

PubMed

Bauer, Martin; Trahms, Lutz; Sander, Tilmann

2015-04-01

The detection limits for cortical and brain stem sources associated with the auditory pathway are examined in order to analyse brain responses at the limits of the audible frequency range. The results obtained from this study are also relevant to other issues of auditory brain research. A complementary approach consisting of recordings of magnetoencephalographic (MEG) data and simulations of magnetic field distributions is presented in this work. A biomagnetic phantom consisting of a spherical volume filled with a saline solution and four current dipoles is built. The magnetic fields outside of the phantom generated by the current dipoles are then measured for a range of applied electric dipole moments with a planar multichannel SQUID magnetometer device and a helmet MEG gradiometer device. The inclusion of a magnetometer system is expected to be more sensitive to brain stem sources compared with a gradiometer system. The same electrical and geometrical configuration is simulated in a forward calculation. From both the measured and the simulated data, the dipole positions are estimated using an inverse calculation. Results are obtained for the reconstruction accuracy as a function of applied electric dipole moment and depth of the current dipole. We found that both systems can localize cortical and subcortical sources at physiological dipole strength even for brain stem sources. Further, we found that a planar magnetometer system is more suitable if the position of the brain source can be restricted in a limited region of the brain. If this is not the case, a helmet-shaped sensor system offers more accurate source estimation.

Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy.

PubMed

Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

2017-10-05

Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." Original articles and critical reviews on the topics were selected. Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis

PubMed Central

Wang, Shih-Min; Lei, Huan-Yao; Liu, Ching-Chuan

2012-01-01

Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema. PMID:22956971

Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells

PubMed Central

Deng, Peter; Torrest, Audrey; Pollock, Kari; Dahlenburg, Heather; Annett, Geralyn; Nolta, Jan A.; Fink, Kyle D.

2016-01-01

Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells (MSC) to secrete brain-derived neurotrophic factor (BDNF) supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington's disease (HD). There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system. PMID:27335539

Methionine PET/CT Studies In Patients With Cancer

ClinicalTrials.gov

2018-06-15

Brain Tumors and/or Solid Tumors Including; Brain Stem Glioma; High Grade CNS Tumors; Ependymoma; Medulloblastoma; Craniopharyngioma; Low Grade CNS Tumors; Hodgkin Lymphoma; Non Hodgkin Lymphoma; Ewing Sarcoma; Osteosarcoma; Rhabdomyosarcoma; Neuroblastoma; Other

Brain and eyes of Kerygmachela reveal protocerebral ancestry of the panarthropod head.

PubMed

Park, Tae-Yoon S; Kihm, Ji-Hoon; Woo, Jusun; Park, Changkun; Lee, Won Young; Smith, M Paul; Harper, David A T; Young, Fletcher; Nielsen, Arne T; Vinther, Jakob

2018-03-09

Recent discoveries of fossil nervous tissue in Cambrian fossils have allowed researchers to trace the origin and evolution of the complex arthropod head and brain based on stem groups close to the origin of the clade, rather than on extant, highly derived members. Here we show that Kerygmachela from Sirius Passet, North Greenland, a primitive stem-group euarthropod, exhibits a diminutive (protocerebral) brain that innervates both the eyes and frontal appendages. It has been surmised, based on developmental evidence, that the ancestor of vertebrates and arthropods had a tripartite brain, which is refuted by the fossil evidence presented here. Furthermore, based on the discovery of eyes in Kerygmachela, we suggest that the complex compound eyes in arthropods evolved from simple ocelli, present in onychophorans and tardigrades, rather than through the incorporation of a set of modified limbs.

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish.

PubMed

Cacialli, Pietro; Palladino, Antonio; Lucini, Carla

2018-06-01

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Bilateral cerebellar and brain stem infarction resulting from vertebral artery injury following cervical trauma without radiographic damage of the spinal column: a case report.

PubMed

Mimata, Yoshikuni; Murakami, Hideki; Sato, Kotaro; Suzuki, Yoshiaki

2014-01-01

Vertebral artery injury can be a complication of cervical spine injury. Although most cases are asymptomatic, the rare case progresses to severe neurological impairment and fatal outcomes. We experienced a case of bilateral cerebellar and brain stem infarction with fatal outcome resulting from vertebral artery injury associated with cervical spine trauma. A 69-year-old male was admitted to our hospital because of tetraplegia after falling down the stairs and hitting his head on the floor. Marked bony damage of the cervical spine was not apparent on radiographs and CT scans, so the injury was initially considered to be a cervical cord injury without bony damage. However, an intensity change in the intervertebral disc at C5/C6, and a ventral epidural hematoma were observed on MRI. A CT angiogram of the neck showed the right vertebral artery was completely occluded at the C4 level of the spine. Forty-eight hours after injury, the patient lapsed into drowsy consciousness. The cranial CT scan showed a massive low-density area in the bilateral cerebellar hemispheres and brain stem. Anticoagulation was initiated after a diagnosis of the right vertebral artery injury, but the patient developed bilateral cerebellar and brain stem infarction. The patient's brain herniation progressed and the patient died 52 h after injury. We considered that not only anticoagulation but also treatment for thrombosis would have been needed to prevent cranial embolism. We fully realize that early and appropriate treatment are essential to improve the treatment results, and constructing a medical system with a team of orthopedists, radiologists, and neurosurgeons is also very important.

Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation.

PubMed

St John, James A; Walkden, Heidi; Nazareth, Lynn; Beagley, Kenneth W; Ulett, Glen C; Batzloff, Michael R; Beacham, Ifor R; Ekberg, Jenny A K

2016-09-01

Infection with Burkholderia pseudomallei causes melioidosis, a disease with a high mortality rate (20% in Australia and 40% in Southeast Asia). Neurological melioidosis is particularly prevalent in northern Australian patients and involves brain stem infection, which can progress to the spinal cord; however, the route by which the bacteria invade the central nervous system (CNS) is unknown. We have previously demonstrated that B. pseudomallei can infect the olfactory and trigeminal nerves within the nasal cavity following intranasal inoculation. As the trigeminal nerve projects into the brain stem, we investigated whether the bacteria could continue along this nerve to penetrate the CNS. After intranasal inoculation of mice, B. pseudomallei caused low-level localized infection within the nasal cavity epithelium, prior to invasion of the trigeminal nerve in small numbers. B. pseudomallei rapidly invaded the trigeminal nerve and crossed the astrocytic barrier to enter the brain stem within 24 h and then rapidly progressed over 2,000 μm into the spinal cord. To rule out that the bacteria used a hematogenous route, we used a capsule-deficient mutant of B. pseudomallei that does not survive in the blood and found that it also entered the CNS via the trigeminal nerve. This suggests that the primary route of entry is via the nerves that innervate the nasal cavity. We found that actin-mediated motility could facilitate initial infection of the olfactory epithelium. Thus, we have demonstrated that B. pseudomallei can rapidly infect the brain and spinal cord via the trigeminal nerve branches that innervate the nasal cavity. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Postnatal Development of Brain-Derived Neurotrophic Factor (BDNF) and Tyrosine Protein Kinase B (TrkB) Receptor Immunoreactivity in Multiple Brain Stem Respiratory-Related Nuclei of the Rat

PubMed Central

Liu, Qiuli; Wong-Riley, Margaret T.T.

2013-01-01

Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12–13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain-derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma-aminobutyric acid (GABA)ergic neurotransmission, and BDNF is essential for respiratory development. We hypothesized that the excitation-inhibition imbalance during the critical period stemmed from a reduced expression of BDNF and TrkB at that time within respiratory-related nuclei of the brain stem. An in-depth, semiquantitative immunohistochemical study was undertaken in seven respiratory-related brain stem nuclei and one nonrespiratory nucleus in P0–21 rats. The results indicate that the expressions of BDNF and TrkB: 1) in the pre-Bötzinger complex, nucleus ambiguus, commissural and ventrolateral subnuclei of solitary tract nucleus, and retrotrapezoid nucleus/parafacial respiratory group were significantly reduced at P12, but returned to P11 levels by P14; 2) in the lateral paragigantocellular nucleus and parapyramidal region were increased from P0 to P7, but were strikingly reduced at P10 and plateaued thereafter; and 3) in the nonrespiratory cuneate nucleus showed a gentle plateau throughout the first 3 post-natal weeks, with only a slight decline of BDNF expression after P11. Thus, the significant downregulation of both BDNF and TrkB in respiratory-related nuclei during the critical period may form the basis of, or at least contribute to, the inhibitory-excitatory imbalance within the respiratory network during this time. PMID:22678720

Leukemia inhibitory factor in the neuroimmune communication pathways in allergic asthma.

PubMed

Lin, Min-Juan; Lao, Xue-Jun; Liu, Sheng-Ming; Xu, Zhen-Hua; Zou, Wei-Feng

2014-03-20

In the pathogenesis of asthma, central sensitization is suggested to be an important neural mechanism, and neurotrophins and cytokines are likely to be the major mediators in the neuroimmune communication pathways of asthma. However, their impact on the central nervous system in allergic asthma remains unclear. We hypothesize that central neurogenic inflammation develops in the pathogenesis of allergic asthma, and nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are important mediators in its development. An asthma model of rats was established by sensitization and challenged with ovalbumin (OVA). For further confirmation of the role of LIF in neurogenic inflammation, a subgroup was pretreated with intraperitoneally (i.p.) LIF antibody before OVA challenge. The levels of LIF and NGF were measured with reverse transcription and polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry stain in lung tissue, airway-specific dorsal root ganglia (DRG, C7-T5) and brain stem of asthmatic rats, anti-LIF pretreated rats and controls. A significantly increased number of LIF- and NGF-immunoreactive cells were detected in lung tissue, DRG and the brain stem of asthmatic rats. In the asthma group a significantly increase level of mRNA encoding LIF and NGF in lung tissue was detected, but not in DRG and the brain stem. Pretreatment with LIF antibody decreased the level of LIF and NGF in all tissues. LIF is an important mediator in the crosstalk between nerve and immune systems. Our study demonstrate that the increased level of LIF and NGF in DRG and brain stem may be not based on result from de novo synthesis, but rather on result from retrograde nerve transport or passage across the blood-brain-barrier. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Imaging transplanted stem cells in real time using an MRI dual-contrast method

PubMed Central

Ngen, Ethel J.; Wang, Lee; Kato, Yoshinori; Krishnamachary, Balaji; Zhu, Wenlian; Gandhi, Nishant; Smith, Barbara; Armour, Michael; Wong, John; Gabrielson, Kathleen; Artemov, Dmitri

2015-01-01

Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies. PMID:26330231

Stem cells technology: a powerful tool behind new brain treatments.

PubMed

Duru, Lucienne N; Quan, Zhenzhen; Qazi, Talal Jamil; Qing, Hong

2018-06-18

Stem cell research has recently become a hot research topic in biomedical research due to the foreseen unlimited potential of stem cells in tissue engineering and regenerative medicine. For many years, medicine has been facing intense challenges, such as an insufficient number of organ donations that is preventing clinicians to fulfill the increasing needs. To try and overcome this regrettable matter, research has been aiming at developing strategies to facilitate the in vitro culture and study of stem cells as a tool for tissue regeneration. Meanwhile, new developments in the microfluidics technology brought forward emerging cell culture applications that are currently allowing for a better chemical and physical control of cellular microenvironment. This review presents the latest developments in stem cell research that brought new therapies to the clinics and how the convergence of the microfluidics technology with stem cell research can have positive outcomes on the fields of regenerative medicine and high-throughput screening. These advances will bring new translational solutions for drug discovery and will upgrade in vitro cell culture to a new level of accuracy and performance. We hope this review will provide new insights into the understanding of new brain treatments from the perspective of stem cell technology especially regarding regenerative medicine and tissue engineering.

Imaging transplanted stem cells in real time using an MRI dual-contrast method.

PubMed

Ngen, Ethel J; Wang, Lee; Kato, Yoshinori; Krishnamachary, Balaji; Zhu, Wenlian; Gandhi, Nishant; Smith, Barbara; Armour, Michael; Wong, John; Gabrielson, Kathleen; Artemov, Dmitri

2015-09-02

Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies.

Neurophysiologic intraoperative monitoring of the vestibulocochlear nerve.

PubMed

Simon, Mirela V

2011-12-01

Neurosurgical procedures involving the skull base and structures within can pose a significant risk of damage to the brain stem and cranial nerves. This can have life-threatening consequences and/or result in devastating neurologic deficits. Over the past decade, intraoperative neurophysiology has significantly evolved and currently offers a great tool for live monitoring of the integrity of nervous structures. Thus, dysfunction can be identified early and prompt modification of the surgical management or operating conditions, leads to avoidance of permanent structural damage.Along these lines, the vestibulocochlear nerve (CN VIII) and, to a greater extent, the auditory pathways as they pass through the brain stem are especially at risk during cerebelopontine angle (CPA), posterior/middle fossa, or brain stem surgery. CN VIII can be damaged by several mechanisms, from vascular compromise to mechanical injury by stretch, compression, dissection, and heat injury. Additionally, cochlea itself can be significantly damaged during temporal bone drilling, by noise, mechanical destruction, or infarction, and because of rupture, occlusion, or vasospasm of the internal auditory artery.CN VIII monitoring can be successfully achieved by live recording of the function of one of its parts, the cochlear or auditory nerve (AN), using the brain stem auditory evoked potentials (BAEPs), electrocochleography (ECochG), and compound nerve action potentials (CNAPs) of the cochlear nerve.This is a review of these techniques, their principle, applications, methodology, interpretation of the evoked responses, and their change from baseline, within the context of surgical and anesthesia environments, and finally the appropriate management of these changes.

Individual Differences in Working Memory, Nonverbal IQ, and Mathematics Achievement and Brain Mechanisms Associated with Symbolic and Nonsymbolic Number Processing

ERIC Educational Resources Information Center

Gullick, Margaret M.; Sprute, Lisa A.; Temple, Elise

2011-01-01

Individual differences in mathematics performance may stem from domain-general factors like working memory and intelligence. Parietal and frontal brain areas have been implicated in number processing, but the influence of such cognitive factors on brain activity during mathematics processing is not known. The relationship between brain mechanisms…

Copine1 regulates neural stem cell functions during brain development.

PubMed

Kim, Tae Hwan; Sung, Soo-Eun; Cheal Yoo, Jae; Park, Jae-Yong; Yi, Gwan-Su; Heo, Jun Young; Lee, Jae-Ran; Kim, Nam-Soon; Lee, Da Yong

2018-01-01

Copine 1 (CPNE1) is a well-known phospholipid binding protein in plasma membrane of various cell types. In brain cells, CPNE1 is closely associated with AKT signaling pathway, which is important for neural stem cell (NSC) functions during brain development. Here, we investigated the role of CPNE1 in the regulation of brain NSC functions during brain development and determined its underlying mechanism. In this study, abundant expression of CPNE1 was observed in neural lineage cells including NSCs and immature neurons in human. With mouse brain tissues in various developmental stages, we found that CPNE1 expression was higher at early embryonic stages compared to postnatal and adult stages. To model developing brain in vitro, we used primary NSCs derived from mouse embryonic hippocampus. Our in vitro study shows decreased proliferation and multi-lineage differentiation potential in CPNE1 deficient NSCs. Finally, we found that the deficiency of CPNE1 downregulated mTOR signaling in embryonic NSCs. These data demonstrate that CPNE1 plays a key role in the regulation of NSC functions through the activation of AKT-mTOR signaling pathway during brain development. Copyright © 2017 Elsevier Inc. All rights reserved.

Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases.

PubMed

Siddiqi, Faez; Wolfe, John H

2016-10-01

Neurological diseases with genetic etiologies result in the loss or dysfunction of neural cells throughout the CNS. At present, few treatment options exist for the majority of neurogenetic diseases. Stem cell transplantation (SCT) into the CNS has the potential to be an effective treatment modality because progenitor cells may replace lost cells in the diseased brain, provide multiple trophic factors, or deliver missing proteins. This review focuses on the use of SCT in lysosomal storage diseases (LSDs), a large group of monogenic disorders with prominent CNS disease. In most patients the CNS disease results in intellectual disability that is refractory to current standard-of-care treatment. A large amount of preclinical work on brain-directed SCT has been performed in rodent LSD models. Cell types that have been used for direct delivery into the CNS include neural stem cells, embryonic and induced pluripotent stem cells, and mesenchymal stem cells. Hematopoietic stem cells have been an effective therapy for the CNS in a few LSDs and may be augmented by overexpression of the missing gene. Current barriers and potential strategies to improve SCT for translation into effective patient therapies are discussed.

Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells

PubMed Central

Varela, Christine; Denis, Jérôme Alexandre; Polentes, Jérôme; Feyeux, Maxime; Aubert, Sophie; Champon, Benoite; Piétu, Geneviève; Peschanski, Marc; Lefort, Nathalie

2012-01-01

Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. Neural derivatives of human embryonic stem cells (hESCs) are currently being used for cell therapy in 3 clinical trials. However, hESCs are prone to genomic instability, which could limit their clinical utility. Here, we report that neural differentiation of hESCs systematically produced a neural stem cell population that could be propagated for more than 50 passages without entering senescence; this was true for all 6 hESC lines tested. The apparent spontaneous loss of evolution toward normal senescence of somatic cells was associated with a jumping translocation of chromosome 1q. This chromosomal defect has previously been associated with hematologic malignancies and pediatric brain tumors with poor clinical outcome. Neural stem cells carrying the 1q defect implanted into the brains of rats failed to integrate and expand, whereas normal cells engrafted. Our results call for additional quality controls to be implemented to ensure genomic integrity not only of undifferentiated pluripotent stem cells, but also of hESC derivatives that form cell therapy end products, particularly neural lines. PMID:22269325

Prion diseases and adult neurogenesis: how do prions counteract the brain's endogenous repair machinery?

PubMed

Relaño-Ginés, Aroa; Lehmann, Sylvain; Crozet, Carole

2014-01-01

Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy. Adult neurogenesis might be part of the physiological regenerative process, however it might become impaired by the disease's mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.

Targeted Knockdown of Bone Morphogenetic Protein Signaling within Neural Progenitors Protects the Brain and Improves Motor Function following Postnatal Hypoxia-Ischemia

PubMed Central

Dettman, Robert W.; Birch, Derin; Fernando, Augusta; Kessler, John A.; Dizon, Maria L.V.

2018-01-01

Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss. Here, we showed that BMP signaling is upregulated within oligodendroglia of the neonatal brain. We tested the hypothesis that inhibition of BMP signaling specifically within neural progenitor cells (NPCs) is sufficient to protect oligodendroglia. We conditionally deleted the BMP receptor 2 subtype (BMPR2) in NG2-expressing cells after HI. We found that BMPR2 deletion globally protects the brain as assessed by MRI and protects motor function as assessed by digital gait analysis, and that conditional deletion of BMPR2 maintains oligodendrocyte marker expression by immunofluorescence and Western blot and prevents loss of oligodendroglia. Finally, BMPR2 deletion after HI results in an increase in noncompacted myelin. Thus, our data indicate that inhibition of BMP signaling specifically in NPCs may be a tractable strategy to protect the newborn brain from HI. PMID:29324456

Neural stem cells in the immature, but not the mature, subventricular zone respond robustly to traumatic brain injury.

PubMed

Goodus, Matthew T; Guzman, Alanna M; Calderon, Frances; Jiang, Yuhui; Levison, Steven W

2015-01-01

Pediatric traumatic brain injury is a significant problem that affects many children each year. Progress is being made in developing neuroprotective strategies to combat these injuries. However, investigators are a long way from therapies to fully preserve injured neurons and glia. To restore neurological function, regenerative strategies will be required. Given the importance of stem cells in repairing damaged tissues and the known persistence of neural precursors in the subventricular zone (SVZ), we evaluated regenerative responses of the SVZ to a focal brain lesion. As tissues repair more slowly with aging, injury responses of male Sprague Dawley rats at 6, 11, 17, and 60 days of age and C57Bl/6 mice at 14 days of age were compared. In the injured immature animals, cell proliferation in the dorsolateral SVZ more than doubled by 48 h. By contrast, the proliferative response was almost undetectable in the adult brain. Three approaches were used to assess the relative numbers of bona fide neural stem cells, as follows: the neurosphere assay (on rats injured at postnatal day 11, P11), flow cytometry using a novel 4-marker panel (on mice injured at P14) and staining for stem/progenitor cell markers in the niche (on rats injured at P17). Precursors from the injured immature SVZ formed almost twice as many spheres as precursors from uninjured age-matched brains. Furthermore, spheres formed from the injured brain were larger, indicating that the neural precursors that formed these spheres divided more rapidly. Flow cytometry revealed a 2-fold increase in the percentage of stem cells, a 4-fold increase in multipotential progenitor-3 cells and a 2.5-fold increase in glial-restricted progenitor-2/multipotential-3 cells. Analogously, there was a 2-fold increase in the mitotic index of nestin+/Mash1- immunoreactive cells within the immediately subependymal region. As the early postnatal SVZ is predominantly generating glial cells, an expansion of precursors might not necessarily lead to the production of many new neurons. On the contrary, many BrdU+/doublecortin+ cells were observed streaming out of the SVZ into the neocortex 2 weeks after injuries to P11 rats. However, very few new mature neurons were seen adjacent to the lesion 28 days after injury. Altogether, these data indicate that immature SVZ cells mount a more robust proliferative response to a focal brain injury than adult cells, which includes an expansion of stem cells, primitive progenitors and neuroblasts. Nonetheless, this regenerative response does not result in significant neuronal replacement, indicating that new strategies need to be implemented to retain the regenerated neurons and glia that are being produced. © 2014 S. Karger AG, Basel.

A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics.

PubMed

Marmarou, A; Foda, M A; van den Brink, W; Campbell, J; Kita, H; Demetriadou, K

1994-02-01

This report describes the development of an experimental head injury model capable of producing diffuse brain injury in the rodent. A total of 161 anesthetized adult rats were injured utilizing a simple weight-drop device consisting of a segmented brass weight free-falling through a Plexiglas guide tube. Skull fracture was prevented by cementing a small stainless-steel disc on the calvaria. Two groups of rats were tested: Group 1, consisting of 54 rats, to establish fracture threshold; and Group 2, consisting of 107 animals, to determine the primary cause of death at severe injury levels. Data from Group 1 animals showed that a 450-gm weight falling from a 2-m height (0.9 kg-m) resulted in a mortality rate of 44% with a low incidence (12.5%) of skull fracture. Impact was followed by apnea, convulsions, and moderate hypertension. The surviving rats developed decortication flexion deformity of the forelimbs, with behavioral depression and loss of muscle tone. Data from Group 2 animals suggested that the cause of death was due to central respiratory depression; the mortality rate decreased markedly in animals mechanically ventilated during the impact. Analysis of mathematical models showed that this mass-height combination resulted in a brain acceleration of 900 G and a brain compression gradient of 0.28 mm. It is concluded that this simple model is capable of producing a graded brain injury in the rodent without a massive hypertensive surge or excessive brain-stem damage.

The Synapse Project: Engagement in mentally challenging activities enhances neural efficiency.

PubMed

McDonough, Ian M; Haber, Sara; Bischof, Gérard N; Park, Denise C

2015-01-01

Correlational and limited experimental evidence suggests that an engaged lifestyle is associated with the maintenance of cognitive vitality in old age. However, the mechanisms underlying these engagement effects are poorly understood. We hypothesized that mental effort underlies engagement effects and used fMRI to examine the impact of high-challenge activities (digital photography and quilting) compared with low-challenge activities (socializing or performing low-challenge cognitive tasks) on neural function at pretest, posttest, and one year after the engagement program. In the scanner, participants performed a semantic-classification task with two levels of difficulty to assess the modulation of brain activity in response to task demands. The High-Challenge group, but not the Low-Challenge group, showed increased modulation of brain activity in medial frontal, lateral temporal, and parietal cortex-regions associated with attention and semantic processing-some of which were maintained a year later. This increased modulation stemmed from decreases in brain activity during the easy condition for the High-Challenge group and was associated with time committed to the program, age, and cognition. Sustained engagement in cognitively demanding activities facilitated cognition by increasing neural efficiency. Mentally-challenging activities may be neuroprotective and an important element to maintaining a healthy brain into late adulthood.

Inhibitory effect of vasopressin receptor antagonist OPC-31260 on experimental brain oedema induced by global cerebral ischaemia.

PubMed

Molnár, A H; Varga, C; Berkó, A; Rojik, I; Párducz, A; László, F; László, F A

2008-03-01

The effects of the non-peptide vasopressin V(2) receptor antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6 h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma vasopressin level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma vasopressin level was further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal vasopressin V(2) receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

The Synapse Project: Engagement in mentally challenging activities enhances neural efficiency

PubMed Central

McDonough, Ian M.; Haber, Sara; Bischof, Gérard N.; Park, Denise C.

2015-01-01

Purpose: Correlational and limited experimental evidence suggests that an engaged lifestyle is associated with the maintenance of cognitive vitality in old age. However, the mechanisms underlying these engagement effects are poorly understood. We hypothesized that mental effort underlies engagement effects and used fMRI to examine the impact of high-challenge activities (digital photography and quilting) compared with low-challenge activities (socializing or performing low-challenge cognitive tasks) on neural function at pretest, posttest, and one year after the engagement program. Methods: In the scanner, participants performed a semantic-classification task with two levels of difficulty to assess the modulation of brain activity in response to task demands. Results: The High-Challenge group, but not the Low-Challenge group, showed increased modulation of brain activity in medial frontal, lateral temporal, and parietal cortex—regions associated with attention and semantic processing—some of which were maintained a year later. This increased modulation stemmed from decreases in brain activity during the easy condition for the High-Challenge group and was associated with time committed to the program, age, and cognition. Conclusions: Sustained engagement in cognitively demanding activities facilitated cognition by increasing neural efficiency. Mentally-challenging activities may be neuroprotective and an important element to maintaining a healthy brain into late adulthood. PMID:26484698

Caspase inhibitors increase the rate of recovery of neural stem/progenitor cells from post-mortem rat brains stored at room temperature.

PubMed

Hasegawa, Atsuko; Yamada, Chikako; Tani, Miho; Hirano, Shun-ichiro; Tokumoto, Yasuhito; Miyake, Jun

2009-06-01

To match the demand of regenerative medicine for nerve system, collection of stem cells from the post-mortem body is one of the most practical ways. In this study, the storage condition of the post-mortem body was examined. We prepared neural stem/progenitor cells (NSPCs) from post-mortem rat brains stored at different temperatures. When brains were stored at 4 degrees C, for one week, we were able to obtain neurospheres (a spheroid body containing NSPCs) by stimulation of cells with epidermal growth factor (EGF). Incremental increases in storage temperature decreased the rate of appearance of neurospheres. Within 48 h at 15 degrees C, 24 h at 25 degrees C, in both condition, we were able to recover NSPCs from post-mortem rat brains. At 15 degrees C, 90% of neurosphere-forming activity was lost within 24 h. However, even after 24 h at 25 degrees C, 2% neurosphere-forming activity remained. After 6 h of death, there was very little difference between the rates of NSPC recovery at 4 degrees C and 25 degrees C. Addition of caspase inhibitors to both the rat brain storage solution and the NSPC culture medium increased the rate of neurosphere-forming activity. In particular, an inhibitor of caspase-8 activity increased the NSPC recovery rate approximately three-fold, with no accompanying detrimental effects on neural differentiation in vitro.

miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells

PubMed Central

Sun, GuoQiang; Ye, Peng; Murai, Kiyohito; Lang, Ming-Fei; Li, Shengxiu; Zhang, Heying; Li, Wendong; Fu, Chelsea; Yin, Jason; Wang, Allen; Ma, Xiaoxiao; Shi, Yanhong

2012-01-01

miR-137 is a brain-enriched microRNA. Its role in neural development remains unknown. Here we show that miR-137 plays an essential role in controlling embryonic neural stem cell fate determination. miR-137 negatively regulates cell proliferation and accelerates neural differentiation of embryonic neural stem cells. In addition, we show that histone demethylase LSD1, a transcriptional co-repressor of nuclear receptor TLX, is a downstream target of miR-137. In utero electroporation of miR-137 in embryonic mouse brains led to premature differentiation and outward migration of the transfected cells. Introducing a LSD1 expression vector lacking the miR-137 recognition site rescued miR-137-induced precocious differentiation. Furthermore, we demonstrate that TLX, an essential regulator of neural stem cell self-renewal, represses the expression of miR-137 by recruiting LSD1 to the genomic regions of miR-137. Thus, miR-137 forms a feedback regulatory loop with TLX and LSD1 to control the dynamics between neural stem cell proliferation and differentiation during neural development. PMID:22068596

Selection of Brain Metastasis-Initiating Breast Cancer Cells Determined by Growth on Hard Agar

PubMed Central

Guo, Lixia; Fan, Dominic; Zhang, Fahao; Price, Janet E.; Lee, Ju-Seog; Marchetti, Dario; Fidler, Isaiah J.; Langley, Robert R.

2011-01-01

An approach that facilitates rapid isolation and characterization of tumor cells with enhanced metastatic potential is highly desirable. Here, we demonstrate that plating GI-101A human breast cancer cells on hard (0.9%) agar selects for the subpopulation of metastasis-initiating cells. The agar-selected cells, designated GI-AGR, were homogeneous for CD44+ and CD133+ and five times more invasive than the parental GI-101A cells. Moreover, mice injected with GI-AGR cells had significantly more experimental brain metastases and shorter overall survival than did mice injected with GI-101A cells. Comparative gene expression analysis revealed that GI-AGR cells were markedly distinct from the parental cells but shared an overlapping pattern of gene expression with the GI-101A subline GI-BRN, which was generated by repeated in vivo recycling of GI-101A cells in an experimental brain metastasis model. Data mining on 216 genes shared between GI-AGR and GI-BRN breast cancer cells suggested that the molecular phenotype of these cells is consistent with that of cancer stem cells and the aggressive basal subtype of breast cancer. Collectively, these results demonstrate that analysis of cell growth in a hard agar assay is a powerful tool for selecting metastasis-initiating cells in a heterogeneous population of breast cancer cells, and that such selected cells have properties similar to those of tumor cells that are selected based on their potential to form metastases in mice. PMID:21514446

Direct and efficient transfection of mouse neural stem cells and mature neurons by in vivo mRNA electroporation.

PubMed

Bugeon, Stéphane; de Chevigny, Antoine; Boutin, Camille; Coré, Nathalie; Wild, Stefan; Bosio, Andreas; Cremer, Harold; Beclin, Christophe

2017-11-01

In vivo brain electroporation of DNA expression vectors is a widely used method for lineage and gene function studies in the developing and postnatal brain. However, transfection efficiency of DNA is limited and adult brain tissue is refractory to electroporation. Here, we present a systematic study of mRNA as a vector for acute genetic manipulation in the developing and adult brain. We demonstrate that mRNA electroporation is far more efficient than DNA electroporation, and leads to faster and more homogeneous protein expression in vivo Importantly, mRNA electroporation allows the manipulation of neural stem cells and postmitotic neurons in the adult brain using minimally invasive procedures. Finally, we show that this approach can be efficiently used for functional studies, as exemplified by transient overexpression of the neurogenic factor Myt1l and by stably inactivating Dicer nuclease in vivo in adult born olfactory bulb interneurons and in fully integrated cortical projection neurons. © 2017. Published by The Company of Biologists Ltd.

Blood-brain barrier-supported neurogenesis in healthy and diseased brain.

PubMed

Pozhilenkova, Elena A; Lopatina, Olga L; Komleva, Yulia K; Salmin, Vladimir V; Salmina, Alla B

2017-05-24

Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain.

PubMed

Emborg, Marina E; Liu, Yan; Xi, Jiajie; Zhang, Xiaoqing; Yin, Yingnan; Lu, Jianfeng; Joers, Valerie; Swanson, Christine; Holden, James E; Zhang, Su-Chun

2013-03-28

The generation of induced pluripotent stem cells (iPSCs) opens up the possibility for personalized cell therapy. Here, we show that transplanted autologous rhesus monkey iPSC-derived neural progenitors survive for up to 6 months and differentiate into neurons, astrocytes, and myelinating oligodendrocytes in the brains of MPTP-induced hemiparkinsonian rhesus monkeys with a minimal presence of inflammatory cells and reactive glia. This finding represents a significant step toward personalized regenerative therapies. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Grounded understanding of abstract concepts: The case of STEM learning.

PubMed

Hayes, Justin C; Kraemer, David J M

2017-01-01

Characterizing the neural implementation of abstract conceptual representations has long been a contentious topic in cognitive science. At the heart of the debate is whether the "sensorimotor" machinery of the brain plays a central role in representing concepts, or whether the involvement of these perceptual and motor regions is merely peripheral or epiphenomenal. The domain of science, technology, engineering, and mathematics (STEM) learning provides an important proving ground for sensorimotor (or grounded) theories of cognition, as concepts in science and engineering courses are often taught through laboratory-based and other hands-on methodologies. In this review of the literature, we examine evidence suggesting that sensorimotor processes strengthen learning associated with the abstract concepts central to STEM pedagogy. After considering how contemporary theories have defined abstraction in the context of semantic knowledge, we propose our own explanation for how body-centered information, as computed in sensorimotor brain regions and visuomotor association cortex, can form a useful foundation upon which to build an understanding of abstract scientific concepts, such as mechanical force. Drawing from theories in cognitive neuroscience, we then explore models elucidating the neural mechanisms involved in grounding intangible concepts, including Hebbian learning, predictive coding, and neuronal recycling. Empirical data on STEM learning through hands-on instruction are considered in light of these neural models. We conclude the review by proposing three distinct ways in which the field of cognitive neuroscience can contribute to STEM learning by bolstering our understanding of how the brain instantiates abstract concepts in an embodied fashion.

Ochratoxin A at nanomolar concentration perturbs the homeostasis of neural stem cells in highly differentiated but not in immature three-dimensional brain cell cultures.

PubMed

Zurich, Marie-Gabrielle; Honegger, Paul

2011-08-28

Ochratoxin A (OTA), a fungal contaminant of basic food commodities, is known to be highly cytotoxic, but the pathways underlying adverse effects at subcytotoxic concentrations remain to be elucidated. Recent reports indicate that OTA affects cell cycle regulation. Therefore, 3D brain cell cultures were used to study OTA effects on mitotically active neural stem/progenitor cells, comparing highly differentiated cultures with their immature counterparts. Changes in the rate of DNA synthesis were related to early changes in the mRNA expression of neural stem/progenitor cell markers. OTA at 10nM, a concentration below the cytotoxic level, was ineffective in immature cultures, whereas in mature cultures it significantly decreased the rate of DNA synthesis together with the mRNA expression of key transcriptional regulators such as Sox2, Mash1, Hes5, and Gli1; the cell cycle activator cyclin D2; the phenotypic markers nestin, doublecortin, and PDGFRα. These effects were largely prevented by Sonic hedgehog (Shh) peptide (500ngml(-1)) administration, indicating that OTA impaired the Shh pathway and the Sox2 regulatory transcription factor critical for stem cell self-renewal. Similar adverse effects of OTA in vivo might perturb the regulation of stem cell proliferation in the adult brain and in other organs exhibiting homeostatic and/or regenerative cell proliferation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

ADHD Experts Fear Brain-Growth Study Being Misconstrued

ERIC Educational Resources Information Center

Viadero, Debra

2007-01-01

This article reports on the results of a groundbreaking brain-imaging study suggesting that attention deficit hyperactivity disorder stems from delayed brain maturation. Implicit in some of the news coverage was the hopeful idea that many--even most--children eventually grow out of the disorder. But that's not exactly true, according to a…

Mind, Brain and Education: A Decade of Evolution

ERIC Educational Resources Information Center

Schwartz, Marc

2015-01-01

This article examines the evolution of Mind, Brain, and Education (MBE), the field, alongside that of the International Mind, Brain and Education Society (IMBES). The reflections stem mostly from my observations while serving as vice president, president-elect, and president of IMBES during the past 10 years. The article highlights the evolution…

Syngeneic Transplantation of Olfactory Ectomesenchymal Stem Cells Restores Learning and Memory Abilities in a Rat Model of Global Cerebral Ischemia.

PubMed

Veron, Antoine D; Bienboire-Frosini, Cécile; Girard, Stéphane D; Sadelli, Kevin; Stamegna, Jean-Claude; Khrestchatisky, Michel; Alexis, Jennifer; Pageat, Patrick; Asproni, Pietro; Mengoli, Manuel; Roman, François S

2018-01-01

Stem cells are considered as promising tools to repair diverse tissue injuries. Among the different stem cell types, the "olfactory ectomesenchymal stem cells" (OE-MSCs) located in the adult olfactory mucosa stand as one of the best candidates. Here, we evaluated if OE-MSC grafts could decrease memory impairments due to ischemic injury. OE-MSCs were collected from syngeneic F344 rats. After a two-step global cerebral ischemia, inducing hippocampal lesions, learning abilities were evaluated using an olfactory associative discrimination task. Cells were grafted into the hippocampus 5 weeks after injury and animal's learning abilities reassessed. Rats were then sacrificed and the brains collected for immunohistochemical analyses. We observed significant impairments in learning and memory abilities following ischemia. However, 4 weeks after OE-MSC grafts, animals displayed learning and memory performances similar to those of controls, while sham rats did not improve them. Immunohistochemical analyses revealed that grafts promoted neuroblast and glial cell proliferation, which could permit to restore cognitive functions. These results demonstrated, for the first time, that syngeneic transplantations of OE-MSCs in rats can restore cognitive abilities impaired after brain injuries and provide support for the development of clinical studies based on grafts of OE-MSCs in amnesic patients following brain injuries.

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions

PubMed Central

Ming, Guo-li; Song, Hongjun

2011-01-01

Summary Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade. PMID:21609825

miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4

PubMed Central

Okuda, Hiroshi; Xing, Fei; Pandey, Puspa R; Sharma, Sambad; Watabe, Misako; Pai, Sudha K.; Mo, Yin-Yuan; Iiizumi-Gairani, Megumi; Hirota, Shigeru; Liu, Yin; Wu, Kerui; Pochampally, Radhika; Watabe, Kounosuke

2012-01-01

Despite significant improvement in survival rates of breast cancer patients, prognosis of metastatic disease is still dismal. Cancer stem-like cells (CSCs) are considered to play a role in metastatic progression of breast cancer; however, the exact pathological role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24−/CD44+/ESA+) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ specific manner. The results of our microRNA profile analysis for these cells revealed that CSCs that are highly metastatic to bone and brain expressed significantly lower level of miR-7 and that this microRNA was capable of modulating one of the essential genes for induced pluripotent stem cell, KLF4. Interestingly, high expression of KLF4 was significantly and inversely correlated to brain- but not bone-metastasis free survival of breast cancer patients, and we indeed found that the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in our animal model. We also examined the expression of miR-7 and KLF4 in brain-metastatic lesions and found that these genes were significantly down- or up-regulated, respectively, in the tumor cells in brain. Furthermore, the results of our in vitro experiments indicate that miR-7 attenuates the abilities of invasion and self-renewal of CSCs by modulating KLF4 expression. These results suggest that miR-7 and KLF4 may serve as biomarkers or therapeutic targets for brain metastasis of breast cancer. PMID:23384942

Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy

PubMed Central

Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

2017-01-01

Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. Data Sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: “stem cells,” “hypoxic preconditioning,” “ischemic preconditioning,” and “cell transplantation.” Study Selection: Original articles and critical reviews on the topics were selected. Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications. PMID:28937044

No pain, no gain: lack of exercise obstructs neurogenesis.

PubMed

Watson, Nate; Ji, Xunming; Yasuhara, Takao; Date, Isao; Kaneko, Yuji; Tajiri, Naoki; Borlongan, Cesar V

2015-01-01

Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress-related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of "increased" exercise on neurogenesis, the reverse paradigm involving "lack of exercise," which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to reveal how in vivo stimulation, or lack thereof, alters the stem cell microenvironment are needed to begin to develop treatment strategies for enhancing neurogenesis in bedridden patients.

Insights into the Biology and Therapeutic Applications of Neural Stem Cells

PubMed Central

Harris, Lachlan; Zalucki, Oressia; Piper, Michael; Heng, Julian Ik-Tsen

2016-01-01

The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the diversity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease. PMID:27069486

The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor

PubMed Central

Zuccarini, Mariachiara; Giuliani, Patricia; Ziberi, Sihana; Carluccio, Marzia; Di Iorio, Patrizia; Caciagli, Francesco

2018-01-01

Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM. PMID:29462960

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

PubMed

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

Impacts of Professional Development in Integrated STEM Education on Teacher Self-Efficacy, Outcome Expectancy, and Stem Career Awareness

NASA Astrophysics Data System (ADS)

Knowles, J. Geoff

This research analyzed the effects of teacher professional development and lesson implementation in integrated Science, Technology, Engineering, and Math (STEM) on: 1.) Teacher self-efficacy and their confidence to teach specific STEM subjects; 2.) Teaching outcome expectancy beliefs concerning the impact of actions by teachers on student learning; and 3.) Teacher awareness of STEM careers. High school science and technology education teachers participating in the Teachers and Researchers Advancing Integrated Lessons in STEM (TRAILS) project experimental group attended a ten-day summer professional development institute designed to educate teachers in using an integrated STEM education model to implement integrated STEM lessons. The research design utilized a quasi-experimental nonequivalent comparison group design that incorporated an experimental group and an untreated comparison group with both pretest, posttest, and delayed posttest assessments on non-randomized participants. Teacher self-efficacy has been identified as a key factor in effective teaching and student learning, and teacher awareness of STEM careers impacts students as they consider career choices. The T-STEM Survey for teachers was given for the pretest and posttest assessments to measure attitudes and beliefs toward the specific constructs of this study. Significant effects of the TRAILS professional development were found in the teacher group (experimental or comparison) and teacher subject (technology or science) in pretest and posttest scores using cumulative link models for the constructs of teacher self-efficacy and beliefs to teach STEM subjects, teacher outcome expectancy beliefs, and teacher awareness of STEM careers. Effect sizes ranged from small to large varying by construct and assessment time. Highly significant p-values and effect sizes revealed impacts on science teachers were greater when teacher subject groups were analyzed separately.

Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy.

PubMed

Molina, Ezequiel J; Palma, Jon; Gupta, Dipin; Torres, Denise; Gaughan, John P; Houser, Steven; Macha, Mahender

2008-02-01

In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery of mesenchymal stem cells on hemodynamic performance, exercise capacity, systemic inflammation, and left ventricular reverse remodeling. Sprague-Dawley rats underwent aortic banding and were followed up by echocardiographic scanning. After a decrease in fractional shortening of 25% from baseline, animals were randomized to intracoronary injection of mesenchymal stem cells (MSC group; n = 28) or phosphate-buffered saline solution (control group; n = 20). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of inflammatory markers were performed before the rats were humanely killed on postoperative day 7, 14, 21, or 28. Injection of mesenchymal stem cells improved systolic function in the MSC group compared with the control group (mean +/- standard deviation: maximum dP/dt 3048 +/- 230 mm Hg/s vs 2169 +/- 97 mm Hg/s at 21 days and 3573 +/- 741 mm Hg/s vs 1363 +/- 322 mm Hg/s at 28 days: P < .001). Time to exhaustion was similarly increased in the MSC group compared with controls (487 +/- 35 seconds vs 306 +/- 27 seconds at 28 days; P < .01). Serum levels of interleukins 1 and 6, tumor necrosis factor-alpha, and brain natriuretic peptide-32 were significantly decreased in animals treated with mesenchymal stem cells. Stem cell transplantation improved left ventricular fractional shortening at 21 and 28 days. Left ventricular end-systolic and end-diastolic diameters were also improved at 28 days. In this model of pressure overload hypertrophy, intracoronary delivery of mesenchymal stem cells during heart failure was associated with an improvement in hemodynamic performance, maximal exercise tolerance, systemic inflammation, and left ventricular reverse remodeling. This study suggests a potential role of this treatment strategy for the management of hypertrophic heart failure resulting from pressure overload.

Distribution of calcium channel Ca(V)1.3 immunoreactivity in the rat spinal cord and brain stem.

PubMed

Sukiasyan, N; Hultborn, H; Zhang, M

2009-03-03

The function of local networks in the CNS depends upon both the connectivity between neurons and their intrinsic properties. An intrinsic property of spinal motoneurons is the presence of persistent inward currents (PICs), which are mediated by non-inactivating calcium (mainly Ca(V)1.3) and/or sodium channels and serve to amplify neuronal input signals. It is of fundamental importance for the prediction of network function to determine the distribution of neurons possessing the ion channels that produce PICs. Although the distribution pattern of Ca(V)1.3 immunoreactivity (Ca(V)1.3-IR) has been studied in some specific central nervous regions in some species, so far no systematic investigations have been performed in both the rat spinal cord and brain stem. In the present study this issue was investigated by immunohistochemistry. The results indicated that the Ca(V)1.3-IR neurons were widely distributed across different parts of the spinal cord and the brain stem although with variable labeling intensities. In the spinal gray matter large neurons in the ventral horn (presumably motoneurons) tended to display higher levels of immunoreactivity than smaller neurons in the dorsal horn. In the white matter, a subset of glial cells labeled by an oligodendrocyte marker was also Ca(V)1.3-positive. In the brain stem, neurons in the motor nuclei appeared to have higher levels of immunoreactivity than those in the sensory nuclei. Moreover, a number of nuclei containing monoaminergic cells, for example the locus coeruleus, were also strongly immunoreactive. Ca(V)1.3-IR was consistently detected in the neuronal perikarya regardless of the neuronal type. However, in the large neurons in the spinal ventral horn and the cranial motor nuclei the Ca(V)1.3-IR was clearly detectable in first and second order dendrites. These results indicate that in the rat spinal cord and brain stem Ca(V)1.3 is probably a common calcium channel used by many kinds of neurons to facilitate the neuronal information processing via certain intracellular mechanisms, for instance, PICs.

Blockade of brain stem gap junctions increases phrenic burst frequency and reduces phrenic burst synchronization in adult rat.

PubMed

Solomon, Irene C; Chon, Ki H; Rodriguez, Melissa N

2003-01-01

Recent investigations have examined the influence of gap junctional communication on generation and modulation of respiratory rhythm and inspiratory motoneuron synchronization in vitro using transverse medullary slice and en bloc brain stem-spinal cord preparations obtained from neonatal (1-5 days postnatal) mice. Gap junction proteins, however, have been identified in both neurons and glia in brain stem regions implicated in respiratory control in both neonatal and adult rodents. Here, we used an in vitro arterially perfused rat preparation to examine the role of gap junctional communication on generation and modulation of respiratory rhythm and inspiratory motoneuron synchronization in adult rodents. We recorded rhythmic inspiratory motor activity from one or both phrenic nerves before and during pharmacological blockade (i.e., uncoupling) of brain stem gap junctions using carbenoxolone (100 microM), 18alpha-glycyrrhetinic acid (25-100 microM), 18beta-glycyrrhetinic acid (25-100 microM), octanol (200-300 microM), or heptanol (200 microM). During perfusion with a gap junction uncoupling agent, we observed an increase in the frequency of phrenic bursts (~95% above baseline frequency; P < 0.001) and a decrease in peak amplitude of integrated phrenic nerve discharge (P < 0.001). The increase in frequency of phrenic bursts resulted from a decrease in both T(I) (P < 0.01) and T(E) (P < 0.01). In addition, the pattern of phrenic nerve discharge shifted from an augmenting discharge pattern to a "bell-shaped" or square-wave discharge pattern in most experiments. Spectral analyses using a fast Fourier transform (FFT) algorithm revealed a reduction in the peak power of both the 40- to 50-Hz peak (corresponding to the MFO) and 90- to 110-Hz peak (corresponding to the HFO) although spurious higher frequency activity (> or =130 Hz) was observed, suggesting an overall loss or reduction in inspiratory-phase synchronization. Although additional experiments are required to identify the specific brain stem regions and cell types (i.e., neurons, glia) mediating the observed modulations in phrenic motor output, these findings suggest that gap junction communication modulates generation of respiratory rhythm and inspiratory motoneuron synchronization in adult rodents in vitro.

Rebound nystagmus: EOG analysis of a case with a floccular tumour.

PubMed Central

Yamazaki, A; Zee, D S

1979-01-01

Eye movements were recorded and quantitatively analysed in a patient with a tumour initially involving the cerebellar flocculus. Ocular motor abnormalities included (1) impaired smooth pursuit, (2) impaired cancellation of the vestibulo-ocular reflex when fixating an object rotating with the head, and (3) gaze paretic and rebound nystagmus. Comparable findings have been reported in monkeys with experimental floccular lesions. The rebound nystagmus (but not the other ocular motor abnormalities) disappeared when the tumour appeared to invade the brain stem in the region near the vestibular nuclei. This finding suggests that the floccular lesion unmasked a bias which created rebound nystagmus and that the bias probably arose in the vestibular nuclei. PMID:508695

Novel potential for the management of Alzheimer disease.

PubMed

Ginter, E; Simko, V; Weinrebova, D; Ladecka, Z

2015-01-01

Pathologic characteristics of Alzheimer disease (AD) are β-amyloid (Aβ) plaques, neurofibrillary tangles (NFT) and neurodegeneration. Currently, there is no cure for AD. Cilostazol, a selective inhibitor of type 3 phosphodiesterase, is likely to be a promising agent for AD. In the brain of the experimental animals it significantly reduced the Aβ amyloid plaques. Initial clinical reports on the effect of Cilostazol in AD patients are promising. In mice, stem cells favourably influence the pathogenetic process critical in AD, by reducing deposits of Aβ plaques. Clinical trials of the drug, called Betablock, are already underway in Britain. Successful management and resolution of AD in man will still require further intensive research (Fig. 4, Ref. 11).

[Morphometry of giant multipolar neurons of the brain stem reticular formation in rats on board the Kosmos-1667 biosatellite].

PubMed

Belichenko, P V; Leontovich, T A

1989-05-01

Giant multipolar neurons of nucleus reticularis gigantocellularis of rats which had been kept on board the biosatellite "Kosmos-1667" were morphometrically studied. There was a trend towards the increase in the cellular surface, the maximum diameter of dendritic field, the volume of the whole dendritic territory in the test group ad in the control experimental group kept on the earth. A reliable decrease in dendritic mass oriented to nucleus vestibularis and an increase in dendritic mass oriented to the midline were also found in test group, as compared to 3 control groups. Our data were discussed in the light of nervous tissue plasticity in adult mammals.

An indirect component in the evoked compound action potential of the vagal nerve.

PubMed

Ordelman, Simone C M A; Kornet, Lilian; Cornelussen, Richard; Buschman, Hendrik P J; Veltink, Peter H

2010-12-01

The vagal nerve plays a vital role in the regulation of the cardiovascular system. It not only regulates the heart but also sends sensory information from the heart back to the brain. We hypothesize that the evoked vagal nerve compound action potential contains components that are indirect via the brain stem or coming via the neural network on the heart. In an experimental study of 15 pigs, we identified four components in the evoked compound action potentials. The fourth component was found to be an indirect component, which came from the periphery. The latency of the indirect component increased when heart rate and contractility were decreased by burst stimulation (P = 0.01; n = 7). When heart rate and contractility were increased by dobutamine administration, the latency of the indirect component decreased (P = 0.01; n = 9). This showed that the latency of the indirect component of the evoked compound action potentials may relate to the state of the cardiovascular system.

Survival rates and prognostic predictors of high grade brain stem gliomas in childhood: a systematic review and meta-analysis.

PubMed

Hassan, Hadeel; Pinches, Anne; Picton, Susan V; Phillips, Robert S

2017-10-01

Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included. Meta-analysis showed 1 year overall survival (OS) of 41% (95% confidence interval (CI) 38-44%, I-sq 52%, 2083 participants), 2 year OS of 15.3% (95% confidence interval 12-20%, I-sq 73.1%, 1329 participants) and 3 year OS of 7.3% (95% confidence interval 5.2-10%, I-sq 26%, 584 participants). Meta-analyses of median overall survival results was not possible due to the lack of reported measures of variance. Subgroup analysis comparing date of study, classification of tumor, use of temozolomide, non-standard interventions or phase 1/2 versus other studies demonstrated no difference in survival outcomes. There was insufficient data to undertake subgroup meta-analysis of patient age, duration of symptoms, K27M histone mutations and AVCR1 mutations. Survival outcomes of high grade brain stem gliomas have remained very poor, and do not clearly vary according to classification, phase of study or use of different therapeutic interventions. Future studies should harmonize outcome and prognostic variable reporting to enable accurate meta-analysis and better exploration of prognosis.

Brain Stem Cavernous Malformations: Operative Nuances of a Less-Invasive Resection Technique.

PubMed

Singh, Harminder; Elarjani, Turki; da Silva, Harley Brito; Shetty, Rakshith; Kim, Louis; Sekhar, Laligam N

2017-12-08

Different operative techniques are reported for the resection of brainstem cavernous malformations (BSCMs). The senior author has previously reported on a less-invasive technique of entering the brain stem with piecemeal removal of BSCMs, especially the deep-seated ones. To present a larger series of these lesions, emphasizing the approach to the brain stem via case selection. We discuss the nuances of the less-invasive operative technique through case illustrations and intraoperative videos. A retrospective review of 46 consecutive cases of BSCMs, with their clinical and radiographic data, was performed. Nine cases were selected to illustrate 7 different operative approaches, and discuss surgical nuances of the less-invasive technique unique to each. Postoperative morbidity, defined as an increase in modified Rankin Scale, was observed in 5 patients (10.9%). A residual BSCM was present in 2 patients (4.3%); both underwent reoperation to remove the remainder. At follow-up of 31.1 ± 27.8 mo, 3 patients experienced recurrence (6.5%). Overall, 65% of our patients improved, 20% stayed the same, and 11% worsened postsurgery. Two patients died, yielding a mortality of 4.3%. Using the less-invasive resection technique for piecemeal BSCM removal, in appropriately selected patients, has yielded comparable to improved patient outcomes over existing large series. In our experience, lateral, anterolateral, and posterolateral approaches are favorable over direct midline (dorsal or ventral) approaches. A thorough understanding of brain-stem safe-entry zones, in conjunction with appropriate approach selection, is key to a good outcome in challenging cases. Copyright © 2017 by the Congress of Neurological Surgeons

Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study

PubMed Central

Monuki, Edwin S.; Powers, James; Schwartz, Phillip H.; Watkins, Paul A.; Shi, Yang; Moser, Ann; Shrier, David A.; Waterham, Hans R.; Nugent, Diane J.; Abdenur, Jose E.

2015-01-01

Objective Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT). Methods We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed. Results Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuroimaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation. Interpretation Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy. PMID:24619150

Mouse embryonic stem cell-derived cells reveal niches that support neuronal differentiation in the adult rat brain.

PubMed

Maya-Espinosa, Guadalupe; Collazo-Navarrete, Omar; Millán-Aldaco, Diana; Palomero-Rivero, Marcela; Guerrero-Flores, Gilda; Drucker-Colín, René; Covarrubias, Luis; Guerra-Crespo, Magdalena

2015-02-01

A neurogenic niche can be identified by the proliferation and differentiation of its naturally residing neural stem cells. However, it remains unclear whether "silent" neurogenic niches or regions suitable for neural differentiation, other than the areas of active neurogenesis, exist in the adult brain. Embryoid body (EB) cells derived from embryonic stem cells (ESCs) are endowed with a high potential to respond to specification and neuralization signals of the embryo. Hence, to identify microenvironments in the postnatal and adult rat brain with the capacity to support neuronal differentiation, we transplanted dissociated EB cells to conventional neurogenic and non-neurogenic regions. Our results show a neuronal differentiation pattern of EB cells that was dependent on the host region. Efficient neuronal differentiation of EB cells occurred within an adjacent region to the rostral migratory stream. EB cell differentiation was initially patchy and progressed toward an even distribution along the graft by 15-21 days post-transplantation, giving rise mostly to GABAergic neurons. EB cells in the striatum displayed a lower level of neuronal differentiation and derived into a significant number of astrocytes. Remarkably, when EB cells were transplanted to the striatum of adult rats after a local ischemic stroke, increased number of neuroblasts and neurons were observed. Unexpectedly, we determined that the adult substantia nigra pars compacta, considered a non-neurogenic area, harbors a robust neurogenic environment. Therefore, neurally uncommitted cells derived from ESCs can detect regions that support neuronal differentiation within the adult brain, a fundamental step for the development of stem cell-based replacement therapies. © 2014 AlphaMed Press.

CCL2 induces neural stem cell proliferation and neuronal differentiation in Niemann-Pick type C mice.

PubMed

Hong, Yu Ri; Lee, Hyun; Park, Min Hee; Lee, Jong Kil; Lee, Ju Youn; Suh, Hwa Deok; Jeong, Min Seock; Bae, Jae-Sung; Jin, Hee Kyung

2015-06-01

Niemann-Pick type C disease (NP-C) is a rare and ultimately fatal lysosomal storage disorder with variable neurologic symptoms. Loss of neuronal function and neuronal cell death occur in the NP-C brain, similar to the findings for other neurodegenerative diseases. Targeting of neuronal cells in the brain therefore represents a potential clinical intervention strategy to reduce the rate of disease progression and improve the quality of life. We previously reported that bone marrow stem cells show a neurogenic effect through CCL2 (also known as monocyte chemoattractant protein-1, MCP-1) secretion in the brains of NP-C mice. However, the direct effect of CCL2 on neurogenesis has not been ascertained. Here, to define neurogenic effects of CCL2 in NP-C, we applied human recombinant CCL2 to neural stem cells (NSCs) derived from NP-C mice. CCL2-treated NSCs showed significantly increased capacity for self-renewal, proliferation and neuronal differentiation. Similar results were observed in the subventricular zone of NP-C mice after CCL2 treatment. Furthermore, infusion of CCL2 into the NP-C mouse brain resulted in reduction of neuroinflammation. Taken together, our results demonstrate that CCL2 is a potential new therapeutic agent for NP-C.

In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.

PubMed

Kokubu, Yasuhiro; Yamaguchi, Tomoko; Kawabata, Kenji

2017-04-29

Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs. Copyright © 2017 Elsevier Inc. All rights reserved.

Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

PubMed

Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

2014-03-01

Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

Expression of amyloid-β protein and amyloid-β precursor protein after primary brain-stem injury in rats.

PubMed

Yang, Shudong; Sun, Rongchao; Zhou, Zhiyi; Zhou, Jing; Liang, Jiabei; Mu, Huijun

2014-09-01

Amyloid-β (Aβ) protein and its precursor, amyloid-β precursor protein (β-APP), have traditionally been used in the diagnosis of Alzheimer disease. Their use in diagnosis of traumatic brain injury by forensic analysis is becoming more widespread. However, to date, no reliable small animal model exists to evaluate these brain injury indicators. To address this, we have studied primary brain-stem injury in rats to assess the appearance of diffuse axonal injury in brain sections and correlate these findings with appearance of Aβ and relative β-APP mRNA levels. Using an EnVision 2-step immunohistochemical staining method to measure axon diameter, we found that there was significant difference in axon diameters within the medulla oblongata and several time points after brain injury, ranging from 3 to 24 hours. In addition, mRNA expression levels of β-APP increased following brain injury, peaking 3 hours following injury and decreasing back to baseline levels by 24 hours after injury. These results suggest that using immunohistochemistry and reverse transcription-polymerase chain reaction to detect changes in Aβ-associated axonal changes and β-APP mRNA levels, respectively, can be useful for the diagnosis of diffuse axonal injury during autopsy at early time points following fatal brain injury.

Long-term cognitive effects of human stem cell transplantation in the irradiated brain.

PubMed

Acharya, Munjal M; Martirosian, Vahan; Christie, Lori-Ann; Limoli, Charles L

2014-09-01

Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition. Athymic nude rats were cranially irradiated (10 Gy) and subjected to intrahippocampal transplantation surgery 2 days later. Human embryonic stem cells (hESC) or human neural stem cells (hNSC) were transplanted, and animals were subjected to cognitive testing on a novel place recognition task 8 months later. Grafting of hNSC was found to provide long lasting cognitive benefits over an 8-month post-irradiation interval. At this protracted time, hNSC grafting improved behavioral performance on a novel place recognition task compared to irradiated animals not receiving stem cells. Engrafted hESC previously shown to be beneficial following a similar task, 1 and 4 months after irradiation, were not found to provide cognitive benefits at 8 months. Our findings suggest that hNSC transplantation promotes the long-term recovery of the irradiated brain, where intrahippocampal stem cell grafting helps to preserve cognitive function.

Disruption of neurogenesis by hypothalamic inflammation in obesity or aging.

PubMed

Purkayastha, Sudarshana; Cai, Dongsheng

2013-12-01

Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components, depending on locations in the brain, poses threat to impaired neurogenesis, neurodegeneration, cognitive loss and energy imbalance. Recent research has identified brain metabolic inflammation via proinflammatory IκB kinase-β (IKKβ) and its downstream nuclear transcription factor NF-κB pathway as a non-classical linker of metabolic and neurodegenerative disorders. Chronic activation of the pathway results in impairment of energy balance and nutrient metabolism, impediment of neurogenesis, neural stem cell proliferation and differentiation, collectively converging on metabolic and cognitive decline. Hypothalamic IKKβ/NF-κB via inflammatory crosstalk between microglia and neurons has been discovered to direct systemic aging by inhibiting the production of gonadotropin-releasing hormone (GnRH) and inhibition of inflammation or GnRH therapy could revert aging related degenerative symptoms at least in part. This article reviews the crucial role of hypothalamic inflammation in affecting neural stem cells which mediates the neurodegenerative mechanisms of causing metabolic derangements as well as aging-associated disorders or diseases.

Embryonic Stem Cell-Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic-Ischemic Mouse Brain.

PubMed

Hawkins, Kate E; Corcelli, Michelangelo; Dowding, Kate; Ranzoni, Anna M; Vlahova, Filipa; Hau, Kwan-Leong; Hunjan, Avina; Peebles, Donald; Gressens, Pierre; Hagberg, Henrik; de Coppi, Paolo; Hristova, Mariya; Guillot, Pascale V

2018-05-01

Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC-MSCs (ES-MSCs from embryonic stem cells) to fetal MSCs (AF-MSCs from the amniotic fluid), demonstrating that ES-MSCs have a superior neuroprotective potential over AF-MSCs in the mouse brain following hypoxia-ischemia. Further, we demonstrate that nuclear factor (NF)-κB-stimulated interleukin (IL)-13 production contributes to an increased in vitro anti-inflammatory potential of ES-MSC-conditioned medium (CM) over AF-MSC-CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell-derived MSCs (iMSCs) exhibit many similarities to ES-MSCs, including enhanced NF-κB signaling and IL-13 production in comparison to AF-MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES-MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic-ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439-449. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

EphA2 Promotes Infiltrative Invasion of Glioma Stem Cells in vivo through Crosstalk with Akt and Regulates Stem Properties

PubMed Central

Miao, Hui; Gale, Nickolas W.; Guo, Hong; Qian, Juan; Petty, Aaron; Kaspar, James; Murphy, Andrew J.; Valenzuela, David M.; Yancopoulos, George; Hambardzumyan, Dolores; Lathia, Justin D.; Rich, Jeremy N.; Lee, Jeongwu; Wang, Bingcheng

2014-01-01

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma (GBM), but the underlying mechanisms remain incompletely understood. Using human glioblastoma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild type littermates. Mechanistically EphA2 knockdown suppressed stem properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem properties in a kinase-independent manner and increased Sox2 expression. In addition to suppressing invasion, disrupting Akt-EphA2 crosstalk attenuated stem marker expression and neurosphere formation while having minimal effects on tumorigenesis, suggesting that the Akt-EphA2 signaling axis contributes to the stem properties. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and contributes to the maintenance of stem properties. PMID:24488013

When stem cells grow old: phenotypes and mechanisms of stem cell aging.

PubMed

Schultz, Michael B; Sinclair, David A

2016-01-01

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. © 2016. Published by The Company of Biologists Ltd.

When stem cells grow old: phenotypes and mechanisms of stem cell aging

PubMed Central

Schultz, Michael B.; Sinclair, David A.

2016-01-01

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. PMID:26732838

Neurogenesis in the embryonic and adult brain: same regulators, different roles

PubMed Central

Urbán, Noelia; Guillemot, François

2014-01-01

Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region. PMID:25505873

Adult Human Neurogenesis: From Microscopy to Magnetic Resonance Imaging

PubMed Central

Sierra, Amanda; Encinas, Juan M.; Maletic-Savatic, Mirjana

2011-01-01

Neural stem cells reside in well-defined areas of the adult human brain and are capable of generating new neurons throughout the life span. In rodents, it is well established that the new born neurons are involved in olfaction as well as in certain forms of memory and learning. In humans, the functional relevance of adult human neurogenesis is being investigated, in particular its implication in the etiopathology of a variety of brain disorders. Adult neurogenesis in the human brain was discovered by utilizing methodologies directly imported from the rodent research, such as immunohistological detection of proliferation and cell-type specific biomarkers in postmortem or biopsy tissue. However, in the vast majority of cases, these methods do not support longitudinal studies; thus, the capacity of the putative stem cells to form new neurons under different disease conditions cannot be tested. More recently, new technologies have been specifically developed for the detection and quantification of neural stem cells in the living human brain. These technologies rely on the use of magnetic resonance imaging, available in hospitals worldwide. Although they require further validation in rodents and primates, these new methods hold the potential to test the contribution of adult human neurogenesis to brain function in both health and disease. This review reports on the current knowledge on adult human neurogenesis. We first review the different methods available to assess human neurogenesis, both ex vivo and in vivo and then appraise the changes of adult neurogenesis in human diseases. PMID:21519376

Isolation, properties and P content of the human brain myosin.

PubMed

Fazekas, S; Ováry, I; Horváth, E; Székessy-Hermann, V; Juhász, P

1982-01-01

KCl-, and NaCl-myosins were prepared from different parts of the central nervous system (CNS). Throughout these experiments P and lipid contents were higher in NaCl-myosins than in KCl-preparations. Both KCl-, and NaCl-myosins have increased lipid and P contents compared with skeletal muscle myosins. When the specimens were separated by a molecular sieve, it was found by chromatographic technique on Sepharose 4B column that the cerebral and cerebellar myosins were composed of two fractions of different molecular mass while the brain stem and spinal cord myosins revealed only a single peak. The myosin fractions' Ca-ATPase activity could be augmented by rabbit muscle actin. The myosin preparations developed filamentous systems and aggregates which could be shown by scanning electron microscopy. All the CNS-myosin preparations could be phosphorylated; however, they were saturated to a different degree and were influenced by the presence or absence of serotonin. The kinetic studies revealed that the phosphate saturation of the brain stem, cerebellar and cerebral myosins depended on the ATP concentration and incubation time. The alkaline hydrolysates of lipid-free human brain myosin preparations contained amino acid phosphates, P-Arg, P-Lys and P-His in different amounts depending on their sources. In response to a phosphorylating mixture only the amount of P-Arg was elevated in the cerebral myosins, P-Arg and P-His in the brain stem preparations, and P-Arg, P-His and the amounts of unidentified compounds in the cerebellar ones.

Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells.

PubMed

Babenko, Valentina A; Silachev, Denis N; Zorova, Ljubava D; Pevzner, Irina B; Khutornenko, Anastasia A; Plotnikov, Egor Y; Sukhikh, Gennady T; Zorov, Dmitry B

2015-09-01

The goal of the present study was to maximally alleviate the negative impact of stroke by increasing the therapeutic potency of injected mesenchymal multipotent stromal cells (MMSCs). To pursue this goal, the intercellular communications of MMSCs and neuronal cells were studied in vitro. As a result of cocultivation of MMSCs and rat cortical neurons, we proved the existence of intercellular contacts providing transfer of cellular contents from one cell to another. We present evidence of intercellular exchange with fluorescent probes specifically occupied by cytosol with preferential transfer from neurons toward MMSCs. In contrast, we observed a reversed transfer of mitochondria (from MMSCs to neural cells). Intravenous injection of MMSCs in a postischemic period alleviated the pathological indexes of a stroke, expressed as a lower infarct volume in the brain and partial restoration of neurological status. Also, MMSCs after cocultivation with neurons demonstrated more profound neuroprotective effects than did unprimed MMSCs. The production of the brain-derived neurotrophic factor was slightly increased in MMSCs, and the factor itself was redistributed in these cells after cocultivation. The level of Miro1 responsible for intercellular traffic of mitochondria was increased in MMSCs after cocultivation. We conclude that the exchange by cellular compartments between neural and stem cells improves MMSCs' protective abilities for better rehabilitation after stroke. This could be used as an approach to enhance the therapeutic benefits of stem cell therapy to the damaged brain. The idea of priming stem cells before practical use for clinical purposes was applied. Thus, cells were preconditioned by coculturing them with the targeted cells (i.e., neurons for the treatment of brain pathological features) before the transfusion of stem cells to the organism. Such priming improved the capacity of stem cells to treat stroke. Some additional minimal study will be required to develop a detailed protocol for coculturing followed by cell separation. ©AlphaMed Press.

A UPLC-TOF/MS-based metabolomics study of rattan stems of Schisandra chinensis effects on Alzheimer's disease rats model.

PubMed

Yang, Bing-You; Tan, Jin-Yan; Liu, Yan; Liu, Bo; Jin, Shuang; Guo, Hong-Wei; Kuang, Hai-Xue

2018-02-01

A UPLC-TOF/MS-based metabolomics method was established to explore the therapeutic mechanisms of rattan stems of S. chinensis (SCS) in Alzheimer's disease (AD). Experimental AD model was induced by intra-hippocampal Aβ 1-42 injection in rats. Cognitive function and oxidative stress condition in brain of AD rats were assessed using Morris water maze tests and antioxidant assays [malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)], respectively. UPLC-TOF/MS combined with multivariate statistical analysis were conducted to study the changes in metabolic networks in serum of rats. The results indicated that the AD model was established successfully and the inducement of Aβ 1-42 caused a decline in spatial learning and memory of rats. The injection of Aβ 1-42 in rat brains significantly elevated the level of MDA, and reduced SOD and GSH-Px activities. In addition, SCS showed significant anti-AD effects on model rats. A total of 30 metabolites were finally identified as potential biomarkers of AD and 14 of them had a significant recovery compared with the AD model after SCS administration. Changes in AD metabolite profiling were restored to different levels through the regulation of 13 pathways. This is first report on the use of the UPLC-TOF/MS-based serum metabolomics method to investigate therapeutic effects of SCS on AD, and enrich potential biomarkers and metabolic networks of AD. Copyright © 2017 John Wiley & Sons, Ltd.

Baroreflex failure in a patient with central nervous system lesions involving the nucleus tractus solitarii

NASA Technical Reports Server (NTRS)

Biaggioni, I.; Whetsell, W. O.; Jobe, J.; Nadeau, J. H.

1994-01-01

Animal studies have shown the importance of the nucleus tractus solitarii, a collection of neurons in the brain stem, in the acute regulation of blood pressure. Impulses arising from the carotid and aortic baroreceptors converge in this center, where the first synapse of the baroreflex is located. Stimulation of the nucleus tractus solitarii provides an inhibitory signal to other brain stem structures, particularly the rostral ventrolateral medulla, resulting in a reduction in sympathetic outflow and a decrease in blood pressure. Conversely, experimental lesions of the nucleus tractus solitarii lead to loss of baroreflex control of blood pressure, sympathetic activation, and severe hypertension in animals. In humans, baroreflex failure due to deafferentation of baroreceptors has been previously reported and is characterized by episodes of severe hypertension and tachycardia. We present a patient with an undetermined process of the central nervous system characterized pathologically by ubiquitous infarctions that were particularly prominent in the nucleus tractus solitarii bilaterally but spared the rostral ventrolateral medulla. Absence of a functioning baroreflex was evidenced by the lack of reflex tachycardia to the hypotensive effects of sodium nitroprusside, exaggerated pressor responses to handgrip and cold pressor test, and exaggerated depressor responses to meals and centrally acting alpha 2-agonists. This clinicopathological correlate suggests that the patient's baroreflex failure can be explained by the unique combination of the destruction of sympathetic inhibitory centers (ie, the nucleus tractus solitarii) and preservation of centers that exert a positive modulation on sympathetic tone (ie, the rostral ventrolateral medulla).

Treatment with acetazolamide of brain-stem and spinal paroxysmal disturbances in multiple sclerosis.

PubMed Central

Voiculescu, V; Pruskauer-Apostol, B; Alecu, C

1975-01-01

Nine cases of multiple sclerosis with paroxysmal disorders were treated with acetazolamide. In most cases a brain-stem origin of the seizures was suggested by their particular pattern: crossed syndromes (facial spasm associated with contralateral weakness of the arm and leg, paroxysmal paraesthesiae in one side of the face and weakness of the contralateral leg), paroxysmal dysarthria, and ataxia. One patient with a Brown-Sequard syndrome complained of paroxysmal paraesthesiae in the lower limbs, for which a spinal origin was admitted. In all patients the paroxysmal disorders were promptly suppressed or markedly reduced by acetazolamide. PMID:1151400

Substance P receptors in brain stem respiratory centers of the rat: regulation of NK1 receptors by hypoxia.

PubMed

Mazzone, S B; Hinrichsen, C F; Geraghty, D P

1997-09-01

Substance P (SP) is a key neurotransmitter involved in the brain stem integration of carotid body chemoreceptor reflexes. In this study, the characteristics and location of SP receptors in the rat brain stem and their regulation by hypoxia were investigated using homogenate radioligand binding and quantitative autoradiography. Specific binding of [125I] Bolton-Hunter SP (BHSP) to brain stem homogenates was saturable (approximately 0.3 nM) and to a single class of high-affinity sites (K(d), 0.16 nM; maximum density of binding sites, 0.43 fmol/mg wet weight tissue). The order of potency of agonists for inhibition of BHSP binding was SP > [Sar9Met(O2)11]SP > neurokinin A > septide > neurokinin B > [Nle10]-neurokinin A(4-10) = senktide, and for nonpeptide antagonists, RP 67580 > CP-96,345 > RP 68651 = CP-96,344, consistent with binding to NK1 receptors. The effect of single and multiple, 5-min bouts of hypoxia (8.5% O2/91.5% N2) on BHSP binding was investigated using quantitative autoradiography. Binding sites were localized to the lateral, medial and commissural nucleus of the solitary tract (NTS), the hypoglossal nucleus, central gray and the spinal trigeminal tract and nucleus (Sp5 and nSp5, respectively). Five min after a single bout of hypoxia, the density of BHSP binding sites had decreased significantly (P < .05) in the medial NTS (-33%) and lateral NTS (-24%) when compared to normoxic controls. However, the normal receptor complement was restored within 60 min of the hypoxic challenge. In the Sp5, a significant decrease (P < .05) in binding was observed 5 min after hypoxia which was still apparent after 60 min. In contrast, the density of BHSP binding sites in the hypoglossal nucleus decreased slowly and was significantly lower (P < .05) than normoxic controls 60 min after hypoxia. Five min after repetitive hypoxia (3 x 5 min bouts), BHSP binding in the NTS was reduced by more than 40%. Studies in homogenates showed that the affinity of SP for BHSP binding sites was not affected by repetitive hypoxia (K(d)s, normoxic, 0.27 nM; hypoxic, 0.24 nM). These data suggest that afferent input from carotid body chemoreceptors may dynamically regulate NK1 receptors in several brain stem nuclei that are intimately involved in stimulating ventilation during hypoxia, and that the time-course of receptor turnover may differ from region to region in the brain stem. The temporary loss of NK1 receptors in the NTS may partly explain why adequate ventilation is often not maintained during hypoxia.

Mercury speciation in brain tissue of polar bears (Ursus maritimus) from the Canadian Arctic.

PubMed

Krey, Anke; Kwan, Michael; Chan, Hing Man

2012-04-01

Methylmercury (MeHg) is a neurotoxicant that has been found at elevated concentrations in the Arctic ecosystem. Little is known about its internal dose in wildlife such as polar bears. We measured concentrations of mercury (Hg) in three different brain regions (cerebellum, frontal lobe and brain stem) of 24 polar bears collected from the Nunavik, Canada between 2000 and 2003. Speciation of Hg was measured by High Performance Liquid Chromatography coupled to Inductively Coupled Plasma Mass Spectroscopy (HPLC-ICP-MS). Concentrations of mean total Hg in brain tissue were up to 625 times lower (0.28 ± 0.07 mg kg(-1) dry weight (dw) in frontal lobe, 0.23 ± 0.07 mg kg(-1) dw in cerebellum and 0.12 ± 0.0 3mg kg(-1) dw in brain stem) than the mean total Hg concentration previously reported in polar bear liver collected from Eastern Baffin Island. Methylmercury (MeHg) accounted for 100% of the Hg found in all three brain regions analyzed. These results suggest that polar bear might reduce the toxic effects of Hg by limiting the uptake into the brain and/or decrease the rate of demethylation so that Hg can be excreted from the brain more easily. The toxicokinetics and the blood-brain-barrier mechanisms of polar bears are still unknown and further research is required. Copyright © 2012 Elsevier Inc. All rights reserved.

Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

PubMed Central

Hill, Eric M.; Petersen, Christian P.

2015-01-01

Mechanisms determining final organ size are poorly understood. Animals undergoing regeneration or ongoing adult growth are likely to require sustained and robust mechanisms to achieve and maintain appropriate sizes. Planarians, well known for their ability to undergo whole-body regeneration using pluripotent adult stem cells of the neoblast population, can reversibly scale body size over an order of magnitude by controlling cell number. Using quantitative analysis, we showed that after injury planarians perfectly restored brain:body proportion by increasing brain cell number through epimorphosis or decreasing brain cell number through tissue remodeling (morphallaxis), as appropriate. We identified a pathway controlling a brain size set-point that involves feedback inhibition between wnt11-6/wntA/wnt4a and notum, encoding conserved antagonistic signaling factors expressed at opposite brain poles. wnt11-6/wntA/wnt4a undergoes feedback inhibition through canonical Wnt signaling but is likely to regulate brain size in a non-canonical pathway independently of beta-catenin-1 and APC. Wnt/Notum signaling tunes numbers of differentiated brain cells in regenerative growth and tissue remodeling by influencing the abundance of brain progenitors descended from pluripotent stem cells, as opposed to regulating cell death. These results suggest that the attainment of final organ size might be accomplished by achieving a balance of positional signaling inputs that regulate the rates of tissue production. PMID:26525673

Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat.

PubMed

Bakhtiary, Mehrdad; Marzban, Mohsen; Mehdizadeh, Mehdi; Joghataei, Mohammad Taghi; Khoei, Samideh; Pirhajati Mahabadi, Vahid; Laribi, Bahareh; Tondar, Mahdi; Moshkforoush, Arash

2010-10-01

Recent clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to compare effect of intravenous injection of bone marrow mesenchymal stem cells (BMSC) and bone marrow hematopoietic stem cell mobilization, induced by granulocyte colony stimulating factor (G-CSF), in rats with a cortical compact device. Forty adult male Wistar rats were injured with controlled cortical impact device and divided randomly into four groups. The treatment groups were injected with 2 × 106 intravenous bone marrow stromal stem cell (n = 10) and also with subcutaneous G-CSF (n = 10) and sham-operation group (n = 10) received PBS and "bromodeoxyuridine (Brdu)" alone, i.p. All injections were performed 1 day after injury into the tail veins of rats. All cells were labeled with Brdu before injection into the tail veins of rats. Functional neurological evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. Statistically, significant improvement in functional outcome was observed in treatment groups compared with control group (P<0.01). mNSS showed no significant difference between the BMSC and G-CSF-treated groups during the study period (end of the trial). Histological analyses showed that Brdu-labeled (MSC) were present in the lesion boundary zone at 42nd day in all injected animals. In our study, we found that administration of a bone marrow-stimulating factor (G-CSF) and BMSC in a TBI model provides functional benefits.

A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy.

PubMed

Yang, Kuo-Liang; Chen, Mei-Fang; Liao, Chia-Hsin; Pang, Cheng-Yoong; Lin, Py-Yu

2009-01-01

We have isolated human neuronal stem cells from exfoliated third molars (wisdom teeth) using a simple and efficient method. The cultured neuronal stem cells (designated tNSC) expressed embryonic and adult stem cell markers, markers for chemotatic factor and its corresponding ligand, as well as neuron proteins. The tNSC expressed genes of Nurr1, NF-M and nestin. They were used to treat middle cerebral artery occlusion (MCAO) surgery-inflicted Sprague-Dawley (SD) rats to assess their therapeutic potential for stroke therapy. For each tNSC cell line, a normal human impacted wisdom tooth was collected from a donor with consent. The tooth was cleaned thoroughly with normal saline. The molar was vigorously shaken or vortexed for 30 min in a 50-mL conical tube with 15-20mL normal saline. The mixture of dental pulp was collected by centrifugation and cultured in a 25-cm(2) tissue culture flask with 4-5mL Medium 199 supplemented with 5-10% fetal calf serum. The tNSC harvested from tissue culture, at a concentration of 1-2x10(5), were suspended in 3 microL saline solution and injected into the right dorsolateral striatum of experimental animals inflicted with MCAO. Behavioral measurements of the tNSC-treated SD rats showed a significant recovery from neurologic dysfunction after MCAO treatment. In contrast, a sham group of SD rats failed to recover from the surgery. Immunohistochemistry analysis of brain sections of the tNSC-treated SD rats showed survival of the transplanted cells. These results suggest that adult neuronal stem cells may be procured from third molars, and tNSC thus cultivated have potential for treatment of stroke-inflicted rats.

miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.

PubMed

Sun, GuoQiang; Ye, Peng; Murai, Kiyohito; Lang, Ming-Fei; Li, Shengxiu; Zhang, Heying; Li, Wendong; Fu, Chelsea; Yin, Jason; Wang, Allen; Ma, Xiaoxiao; Shi, Yanhong

2011-11-08

miR-137 is a brain-enriched microRNA. Its role in neural development remains unknown. Here we show that miR-137 has an essential role in controlling embryonic neural stem cell fate determination. miR-137 negatively regulates cell proliferation and accelerates neural differentiation of embryonic neural stem cells. In addition, we show that the histone lysine-specific demethylase 1 (LSD1), a transcriptional co-repressor of nuclear receptor TLX, is a downstream target of miR-137. In utero electroporation of miR-137 in embryonic mouse brains led to premature differentiation and outward migration of the transfected cells. Introducing a LSD1 expression vector lacking the miR-137 recognition site rescued miR-137-induced precocious differentiation. Furthermore, we demonstrate that TLX, an essential regulator of neural stem cell self-renewal, represses the expression of miR-137 by recruiting LSD1 to the genomic regions of miR-137. Thus, miR-137 forms a feedback regulatory loop with TLX and LSD1 to control the dynamics between neural stem cell proliferation and differentiation during neural development.

Epitranscriptomics: A New Regulatory Mechanism of Brain Development and Function

PubMed Central

Noack, Florian; Calegari, Federico

2018-01-01

Epigenetic modifications of DNA and chromatin are long known to control stem cell differentiation and organ function but the role of similar modifications at the level or regulatory RNAs is just beginning to emerge. Over 160 RNA modifications have been identified but their abundance, distribution and functional significance are not known. The few available maps of RNA modifications indicated their dynamic regulation during somatic stem cell differentiation, brain development and function in adulthood suggesting a hitherto unsuspected layer of regulation both at the level of RNA metabolism and post-transcriptional control of gene expression. The advent of programmable, RNA-specific CRISPR-Cas editing platforms together with the identification of RNA modifying enzymes now offers the opportunity to investigate the functional role of these elusive epitranscriptome changes. Here, we discuss recent insights in studying the most abundant modifications in functional mRNAs and lncRNAs, N6-methyladenosine and 5-(hydroxy-)methylcytosine, and their role in regulating somatic stem cell differentiation with particular attention to neural stem cells during mammalian corticogenesis. An outlook on novel CRISPR-Cas based systems that allow stem cell reprogramming by epitranscriptome-editing will also be discussed. PMID:29515357

Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis.

PubMed

Trubiani, Oriana; Giacoppo, Sabrina; Ballerini, Patrizia; Diomede, Francesca; Piattelli, Adriano; Bramanti, Placido; Mazzon, Emanuela

2016-01-04

Multiple sclerosis is a demyelinating disease mostly of autoimmune origin that affects and damages the central nervous system, leading to a disabling condition. The aim of the present study was to investigate whether administration of mesenchymal stem cells from human periodontal ligament (hPDLSCs) could ameliorate multiple sclerosis progression by exerting neuroprotective effects in an experimental model of autoimmune encephalomyelitis (EAE). EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in C57BL/6 mice. After immunization, mice were observed every 48 hours for signs of EAE and weight loss. At the onset of disease, approximately 14 days after immunization, EAE mice were subjected to a single intravenous injection of hPDLSCs (10(6) cells/150 μl) into the tail vein. At the point of animal sacrifice on day 56 after EAE induction, spinal cord and brain tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Achieved results reveal that treatment with hPDLSCs may exert neuroprotective effects against EAE, diminishing both clinical signs and histological score typical of the disease (lymphocytic infiltration and demyelination) probably through the production of neurotrophic factors (results focused on brain-derived neurotrophic factor and nerve growth factor expression). Furthermore, administration of hPDLSCs modulates expression of inflammatory key markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-10, glial fibrillary acidic protein, Nrf2 and Foxp3), the release of CD4 and CD8α T cells, and the triggering of apoptotic death pathway (data shown for cleaved caspase 3, p53 and p21). In light of the achieved results, transplantation of hPDLSCs may represent a putative novel and helpful tool for multiple sclerosis treatment. These cells could have considerable implication for future therapies for multiple sclerosis and this study may represent the starting point for further investigations.

Neurotoxicity Associated With Dimethyl Sulfoxide Used in Allogeneic Stem Cell Transplantation.

PubMed

Ataseven, Eda; Tüfekçi, Özlem; Yilmaz, Şebnem; Güleryüz, Handan; Ören, Hale

2017-07-01

Dimethyl sulfoxide (DMSO) is a cryoprotective agent used in storage of frozen stem cells in stem cell transplantation. Central nervous system side effects of DMSO such as epileptic seizures, stroke, transient global amnesia, and temporary leucoencephalopathy are rarely seen. Here, we report a pediatric patient who developed seizures after DMSO-cryopreserved stem cell infusion and whose magnetic resonance imaging of the brain demonstrated parietal and occipital focal cortical T2-signal intensity increase. DMSO toxicity should be kept in mind in patients who received cryopreserved stem cell infusion and magnetic resonance imaging may be helpful in differential diagnosis of central nervous system involvement.

Effects of Intravenous Administration of Human Umbilical Cord Blood Stem Cells in 3-Acetylpyridine-Lesioned Rats

PubMed Central

Calatrava-Ferreras, Lucía; Gonzalo-Gobernado, Rafael; Herranz, Antonio S.; Reimers, Diana; Montero Vega, Teresa; Jiménez-Escrig, Adriano; Richart López, Luis Alberto; Bazán, Eulalia

2012-01-01

Cerebellar ataxias include a heterogeneous group of infrequent diseases characterized by lack of motor coordination caused by disturbances in the cerebellum and its associated circuits. Current therapies are based on the use of drugs that correct some of the molecular processes involved in their pathogenesis. Although these treatments yielded promising results, there is not yet an effective therapy for these diseases. Cell replacement strategies using human umbilical cord blood mononuclear cells (HuUCBMCs) have emerged as a promising approach for restoration of function in neurodegenerative diseases. The aim of this work was to investigate the potential therapeutic activity of HuUCBMCs in the 3-acetylpyridine (3-AP) rat model of cerebellar ataxia. Intravenous administered HuUCBMCs reached the cerebellum and brain stem of 3-AP ataxic rats. Grafted cells reduced 3-AP-induced neuronal loss promoted the activation of microglia in the brain stem, and prevented the overexpression of GFAP elicited by 3-AP in the cerebellum. In addition, HuUCBMCs upregulated the expression of proteins that are critical for cell survival, such as phospho-Akt and Bcl-2, in the cerebellum and brain stem of 3-AP ataxic rats. As all these effects were accompanied by a temporal but significant improvement in motor coordination, HuUCBMCs grafts can be considered as an effective cell replacement therapy for cerebellar disorders. PMID:23150735

Integrated analysis of genetic, behavioral, and biochemical data implicates neural stem cell-induced changes in immunity, neurotransmission and mitochondrial function in Dementia with Lewy Body mice.

PubMed

Lakatos, Anita; Goldberg, Natalie R S; Blurton-Jones, Mathew

2017-03-10

We previously demonstrated that transplantation of murine neural stem cells (NSCs) can improve motor and cognitive function in a transgenic model of Dementia with Lewy Bodies (DLB). These benefits occurred without changes in human α-synuclein pathology and were mediated in part by stem cell-induced elevation of brain-derived neurotrophic factor (BDNF). However, instrastriatal NSC transplantation likely alters the brain microenvironment via multiple mechanisms that may synergize to promote cognitive and motor recovery. The underlying neurobiology that mediates such restoration no doubt involves numerous genes acting in concert to modulate signaling within and between host brain cells and transplanted NSCs. In order to identify functionally connected gene networks and additional mechanisms that may contribute to stem cell-induced benefits, we performed weighted gene co-expression network analysis (WGCNA) on striatal tissue isolated from NSC- and vehicle-injected wild-type and DLB mice. Combining continuous behavioral and biochemical data with genome wide expression via network analysis proved to be a powerful approach; revealing significant alterations in immune response, neurotransmission, and mitochondria function. Taken together, these data shed further light on the gene network and biological processes that underlie the therapeutic effects of NSC transplantation on α-synuclein induced cognitive and motor impairments, thereby highlighting additional therapeutic targets for synucleinopathies.

Brain signatures of early lexical and morphological learning of a new language.

PubMed

Havas, Viktória; Laine, Matti; Rodríguez Fornells, Antoni

2017-07-01

Morphology is an important part of language processing but little is known about how adult second language learners acquire morphological rules. Using a word-picture associative learning task, we have previously shown that a brief exposure to novel words with embedded morphological structure (suffix for natural gender) is enough for language learners to acquire the hidden morphological rule. Here we used this paradigm to study the brain signatures of early morphological learning in a novel language in adults. Behavioural measures indicated successful lexical (word stem) and morphological (gender suffix) learning. A day after the learning phase, event-related brain potentials registered during a recognition memory task revealed enhanced N400 and P600 components for stem and suffix violations, respectively. An additional effect observed with combined suffix and stem violations was an enhancement of an early N2 component, most probably related to conflict-detection processes. Successful morphological learning was also evident in the ERP responses to the subsequent rule-generalization task with new stems, where violation of the morphological rule was associated with an early (250-400ms) and late positivity (750-900ms). Overall, these findings tend to converge with lexical and morphosyntactic violation effects observed in L1 processing, suggesting that even after a short exposure, adult language learners can acquire both novel words and novel morphological rules. Copyright © 2017 Elsevier Ltd. All rights reserved.

Annual Research Review: The Promise of Stem Cell Research for Neuropsychiatric Disorders

ERIC Educational Resources Information Center

Vaccarino, Flora M.; Urban, Alexander Eckehart; Stevens, Hanna E.; Szekely, Anna; Abyzov, Alexej; Grigorenko, Elena L.; Gerstein, Mark; Weissman, Sherman

2011-01-01

The study of the developing brain has begun to shed light on the underpinnings of both early and adult onset neuropsychiatric disorders. Neuroimaging of the human brain across developmental time points and the use of model animal systems have combined to reveal brain systems and gene products that may play a role in autism spectrum disorders,…

Postnatal Neural Stem Cells in Treating Traumatic Brain Injury.

PubMed

Gazalah, Hussein; Mantash, Sarah; Ramadan, Naify; Al Lafi, Sawsan; El Sitt, Sally; Darwish, Hala; Azari, Hassan; Fawaz, Lama; Ghanem, Noël; Zibara, Kazem; Boustany, Rose-Mary; Kobeissy, Firas; Soueid, Jihane

2016-01-01

Traumatic brain injury (TBI) is one of the leading causes of death and disabilities worldwide. It affects approximately 1.5 million people each year and is associated with severe post-TBI symptoms such as sensory and motor deficits. Several neuro-therapeutic approaches ranging from cell therapy interventions such as the use of neural stem cells (NSCs) to drug-based therapies have been proposed for TBI management. Successful cell-based therapies are tightly dependent on reproducible preclinical animal models to ensure safety and optimal therapeutic benefits. In this chapter, we describe the isolation of NSCs from neonatal mouse brain using the neurosphere assay in culture. Subsequently, dissociated neurosphere-derived cells are used for transplantation into the ipsilateral cortex of a controlled cortical impact (CCI) TBI model in C57BL/6 mice. Following intra-cardiac perfusion and brain removal, the success of NSC transplantation is then evaluated using immunofluorescence in order to assess neurogenesis along with gliosis in the ipsilateral coronal brain sections. Behavioral tests including rotarod and pole climbing are conducted to evaluate the motor activity post-treatment intervention.

Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner.

PubMed

Krejciova, Zuzana; Alibhai, James; Zhao, Chen; Krencik, Robert; Rzechorzek, Nina M; Ullian, Erik M; Manson, Jean; Ironside, James W; Head, Mark W; Chandran, Siddharthan

2017-12-04

Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery. © 2017 Krejciova et al.

Brain volume reductions in adolescent heavy drinkers.

PubMed

Squeglia, Lindsay M; Rinker, Daniel A; Bartsch, Hauke; Castro, Norma; Chung, Yoonho; Dale, Anders M; Jernigan, Terry L; Tapert, Susan F

2014-07-01

Brain abnormalities in adolescent heavy drinkers may result from alcohol exposure, or stem from pre-existing neural features. This longitudinal morphometric study investigated 40 healthy adolescents, ages 12-17 at study entry, half of whom (n=20) initiated heavy drinking over the 3-year follow-up. Both assessments included high-resolution magnetic resonance imaging. FreeSurfer was used to segment brain volumes, which were measured longitudinally using the newly developed quantitative anatomic regional change analysis (QUARC) tool. At baseline, participants who later transitioned into heavy drinking showed smaller left cingulate, pars triangularis, and rostral anterior cingulate volume, and less right cerebellar white matter volumes (p<.05), compared to continuous non-using teens. Over time, participants who initiated heavy drinking showed significantly greater volume reduction in the left ventral diencephalon, left inferior and middle temporal gyrus, and left caudate and brain stem, compared to substance-naïve youth (p<.05). Findings suggest pre-existing volume differences in frontal brain regions in future drinkers and greater brain volume reduction in subcortical and temporal regions after alcohol use was initiated. This is consistent with literature showing pre-existing cognitive deficits on tasks recruited by frontal regions, as well as post-drinking consequences on brain regions involved in language and spatial tasks. Published by Elsevier Ltd.

Rebuilding the injured brain: use of MRS in clinical regenerative medicine

NASA Astrophysics Data System (ADS)

Zare, Alina; Weiss, Michael; Gader, Paul

2011-03-01

Hypoxic-Ischemic Encephalopathy (HIE) is the brain manifestation of systemic asphyxia that occurs in 20 out of 1000 births. HIE triggers an immediate neuronal and glial injury leading to necrosis secondary to cellular edema and lysis. Because of this destructive neuronal injury, up to 25% of neonates exhibit severe permanent neuropsychological handicaps in the form of cerebral palsy, with or without associated mental retardation, learning disabilities, or epilepsy. Due to the devastating consequences of HIE, much research has focused on interrupting the cascade of events triggered by HIE. To date, none of these therapies, with the exception of hypothermia, have been successful in the clinical environment. Even in the case of hypothermia, only neonates with mild to moderate HIE respond to therapy. Stem cell therapy offers an attractive potential treatment for HIE. The ability to replace necrotic cells with functional cells could limit the degree of long-term neurological deficits. The neonatal brain offers a unique milieu for stem cell therapy due to its overall plasticity and the continued division of cells in the sub-ventricular zones. New powerful imaging tools allow researchers to track stem cells in vivo post-transplant, as shown in Figure 1. However, neuroimaging still leaves numerous questions unresolved: How can we identify stem cells without using tracking agents, what cells types are destroyed in the brain post injury? What is the final phenotypic fate of transplanted cells? Are the transplanted cells still viable? Do the transplanted cells spare endogenous neuronal tissue? We hypothesize that magnetic resonance spectroscopy (MRS), a broadly used clinical technique that can be performed at the time of a standard MRI scan, can provide answers to these questions when coupled with advanced computational approaches. MRS is widely available clinically, and is a relative measure of different metabolites within the sampled area. These measures are presented as a series of peaks at a particular bandwidth that corresponds to an individual metabolite, such as lactate or creatine, as shown in Figure 2. Currently, the data are only subjectively interpreted by a neuro-radiologist, but hold great potential if they were analyzed in a more objective manner. The overall purpose of the research described here is to develop pattern recognition algorithms for MRS data as a means to detect novel biomarkers or fingerprints of stem cells. Once identified, this technique will be used to identify in vivo transplanted stem cells within the brain.

Targeting the Brain with a Neuroprotective Omega-3 Fatty Acid to Enhance Neurogenesis in Hypoxic Condition in Culture.

PubMed

Lo Van, Amanda; Sakayori, Nobuyuki; Hachem, Mayssa; Belkouch, Mounir; Picq, Madeleine; Fourmaux, Baptiste; Lagarde, Michel; Osumi, Noriko; Bernoud-Hubac, Nathalie

2018-06-01

Docosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA) that is required for proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases, a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with aging or neurodegenerative diseases. In this context, targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases. We previously synthesized a stabilized form of DHA-containing lysophosphatidylcholine a major vector of DHA transportation to the brain, which is 1-acetyl,2-docoshexaenoyl-glycerophosphocholine, named AceDoPC®. Injection of AceDoPC® or DHA after experimental ischemic stroke showed that both molecules had neuroprotective effects but AceDoPC® was the most potent. This study aims to investigate the beneficial effects of DHA either unesterified or esterified within AceDoPC® on a model of neurogenesis in vitro, under physiological or pathological conditions. The effect of protectin DX (PDX, a double lipoxygenase product of DHA) was also tested. We cultured neural stem progenitor cells (NSPCs) derived from the adult mouse brain under normal or hypoxigenic (ischemic) conditions in vitro. Neurogenesis study of cell cultures with AceDoPC® showed enhanced neurogenesis compared to addition of unesterified DHA, PDX, or vehicle control, especially under pathological conditions. Our studies of the potential mechanisms involved in neuroprotection hinted that AceDoPC® neuroprotective and regenerative effects might be due in part to its anti-oxidative effects. These results indicate the potential for novel therapeutics against stroke that target the brain.

Mangiferin decreases inflammation and oxidative damage in rat brain after stress.

PubMed

Márquez, Lucía; García-Bueno, Borja; Madrigal, José L M; Leza, Juan C

2012-09-01

Stress exposure elicits neuroinflammation and oxidative damage in brain, and stress-related neurological and neuropsychiatric diseases have been associated with cell damage and death. Mangiferin (MAG) is a polyphenolic compound abundant in the stem bark of Mangifera indica L. with antioxidant and anti-inflammatory properties in different experimental settings. In this study, the capacity of MAG to prevent neuroinflammation and brain oxidative damage induced by stress exposure was investigated. Young-adult male Wistar rats immobilized during 6 h were administered by oral gavage with increasing doses of MAG (15, 30, and 60 mg/Kg), respectively, 7 days before stress. Prior treatment with MAG prevented all of the following stress-induced effects: (1) increase in glucocorticoids (GCs) and interleukin-1β (IL-1β) plasma levels, (2) loss of redox balance and reduction in catalase brain levels, (3) increase in pro-inflammatory mediators, such as tumor necrosis factor alpha TNF-α and its receptor TNF-R1, nuclear factor-kappa B (NF-κB) and synthesis enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), (4) increase in lipid peroxidation. These multifaceted protective effects suggest that MAG administration could be a new therapeutic strategy in neurological/neuropsychiatric pathologies in which hypothalamic/pituitary/adrenal (HPA) stress axis dysregulation, neuroinflammation, and oxidative damage take place in their pathophysiology.

Significant Artifact Reduction at 1.5T and 3T MRI by the Use of a Cochlear Implant with Removable Magnet: An Experimental Human Cadaver Study

PubMed Central

Wagner, Franca; Wimmer, Wilhelm; Leidolt, Lars; Vischer, Mattheus; Weder, Stefan; Wiest, Roland; Mantokoudis, Georgios; Caversaccio, Marco D.

2015-01-01

Objective Cochlear implants (CIs) are standard treatment for postlingually deafened individuals and prelingually deafened children. This human cadaver study evaluated diagnostic usefulness, image quality and artifacts in 1.5T and 3T magnetic resonance (MR) brain scans after CI with a removable magnet. Methods Three criteria (diagnostic usefulness, image quality, artifacts) were assessed at 1.5T and 3T in five cadaver heads with CI. The brain magnetic resonance scans were performed with and without the magnet in situ. The criteria were analyzed by two blinded neuroradiologists, with focus on image distortion and limitation of the diagnostic value of the acquired MR images. Results MR images with the magnet in situ were all compromised by artifacts caused by the CI. After removal of the magnet, MR scans showed an unequivocal artifact reduction with significant improvement of the image quality and diagnostic usefulness, both at 1.5T and 3T. Visibility of the brain stem, cerebellopontine angle, and parieto-occipital lobe ipsilateral to the CI increased significantly after magnet removal. Conclusions The results indicate the possible advantages for 1.5T and 3T MR scanning of the brain in CI carriers with removable magnets. Our findings support use of CIs with removable magnets, especially in patients with chronic intracranial pathologies. PMID:26200775

Significant Artifact Reduction at 1.5T and 3T MRI by the Use of a Cochlear Implant with Removable Magnet: An Experimental Human Cadaver Study.

PubMed

Wagner, Franca; Wimmer, Wilhelm; Leidolt, Lars; Vischer, Mattheus; Weder, Stefan; Wiest, Roland; Mantokoudis, Georgios; Caversaccio, Marco D

2015-01-01

Cochlear implants (CIs) are standard treatment for postlingually deafened individuals and prelingually deafened children. This human cadaver study evaluated diagnostic usefulness, image quality and artifacts in 1.5T and 3T magnetic resonance (MR) brain scans after CI with a removable magnet. Three criteria (diagnostic usefulness, image quality, artifacts) were assessed at 1.5T and 3T in five cadaver heads with CI. The brain magnetic resonance scans were performed with and without the magnet in situ. The criteria were analyzed by two blinded neuroradiologists, with focus on image distortion and limitation of the diagnostic value of the acquired MR images. MR images with the magnet in situ were all compromised by artifacts caused by the CI. After removal of the magnet, MR scans showed an unequivocal artifact reduction with significant improvement of the image quality and diagnostic usefulness, both at 1.5T and 3T. Visibility of the brain stem, cerebellopontine angle, and parieto-occipital lobe ipsilateral to the CI increased significantly after magnet removal. The results indicate the possible advantages for 1.5T and 3T MR scanning of the brain in CI carriers with removable magnets. Our findings support use of CIs with removable magnets, especially in patients with chronic intracranial pathologies.

Robust phenotyping strategies for evaluation of stem non-structural carbohydrates (NSC) in rice.

PubMed

Wang, Diane R; Wolfrum, Edward J; Virk, Parminder; Ismail, Abdelbagi; Greenberg, Anthony J; McCouch, Susan R

2016-11-01

Rice plants (Oryza sativa) accumulate excess photoassimilates in the form of non-structural carbohydrates (NSCs) in their stems prior to heading that can later be mobilized to supplement photosynthate production during grain-filling. Despite longstanding interest in stem NSC for rice improvement, the dynamics of NSC accumulation, remobilization, and re-accumulation that have genetic potential for optimization have not been systematically investigated. Here we conducted three pilot experiments to lay the groundwork for large-scale diversity studies on rice stem NSC. We assessed the relationship of stem NSC components with 21 agronomic traits in large-scale, tropical yield trials using 33 breeder-nominated lines, established an appropriate experimental design for future genetic studies using a Bayesian framework to sample sub-datasets from highly replicated greenhouse data using 36 genetically diverse genotypes, and used 434 phenotypically divergent rice stem samples to develop two partial least-squares (PLS) models using near-infrared (NIR) spectra for accurate, rapid prediction of rice stem starch, sucrose, and total non-structural carbohydrates. We find evidence that stem reserves are most critical for short-duration varieties and suggest that pre-heading stem NSC is worthy of further experimentation for breeding early maturing rice. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

PTEN, a negative regulator of PI3K/Akt signaling, sustains brain stem cardiovascular regulation during mevinphos intoxication.

PubMed

Tsai, Ching-Yi; Wu, Jacqueline C C; Fang, Chi; Chang, Alice Y W

2017-09-01

Activation of PI3K/Akt signaling, leading to upregulation of nitric oxide synthase II (NOS II)/peroxynitrite cascade in the rostral ventrolateral medulla (RVLM), the brain stem site that maintains blood pressure and sympathetic vasomotor tone, underpins cardiovascular depression induced by the organophosphate pesticide mevinphos. By exhibiting dual-specificity protein- and lipid-phosphatase activity, phosphatase and tensin homolog (PTEN) directly antagonizes the PI3K/Akt signaling by dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate, the lipid product of PI3K. Based on the guiding hypothesis that PTEN may sustain brain stem cardiovascular regulation during mevinphos intoxication as a negative regulator of PI3K/Akt signaling in the RVLM, we aimed in this study to clarify the mechanistic role of PTEN in mevinphos-induced circulatory depression. Microinjection bilaterally of mevinphos (10 nmol) into the RVLM of anesthetized Sprague-Dawley rats induced a progressive hypotension and a decrease in baroreflex-mediated sympathetic vasomotor tone. There was progressive augmentation in PTEN activity as reflected by a decrease in the oxidized form of PTEN in the RVLM during mevinhpos intoxication, without significant changes in the mRNA or protein level of PTEN. Loss-of-function manipulations of PTEN in the RVLM by immunoneutralization, pharmacological blockade or siRNA pretreatment significantly potentiated the increase in Akt activity or NOS II/peroxynitrite cascade in the RVLM, enhanced the elicited hypotension and exacerbated the already reduced baroreflex-mediated sympathetic vasomotor tone. We conclude that augmented PTEN activity via a decrease of its oxidized form in the RVLM sustains brain stem cardiovascular regulation during mevinphos intoxication via downregulation of the NOS II/peroxynitrite cascade as a negative regulator of PI3K/Akt signaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neurochemical excitation of propriospinal neurons facilitates locomotor command signal transmission in the lesioned spinal cord.

PubMed

Zaporozhets, Eugene; Cowley, Kristine C; Schmidt, Brian J

2011-06-01

Previous studies of the in vitro neonatal rat brain stem-spinal cord showed that propriospinal relays contribute to descending transmission of a supraspinal command signal that is capable of activating locomotion. Using the same preparation, the present series examines whether enhanced excitation of thoracic propriospinal neurons facilitates propagation of the locomotor command signal in the lesioned spinal cord. First, we identified neurotransmitters contributing to normal endogenous propriospinal transmission of the locomotor command signal by testing the effect of receptor antagonists applied to cervicothoracic segments during brain stem-induced locomotor-like activity. Spinal cords were either intact or contained staggered bilateral hemisections located at right T1/T2 and left T10/T11 junctions designed to abolish direct long-projecting bulbospinal axons. Serotonergic, noradrenergic, dopaminergic, and glutamatergic, but not cholinergic, receptor antagonists blocked locomotor-like activity. Approximately 73% of preparations with staggered bilateral hemisections failed to generate locomotor-like activity in response to electrical stimulation of the brain stem alone; such preparations were used to test the effect of neuroactive substances applied to thoracic segments (bath barriers placed at T3 and T9) during brain stem stimulation. The percentage of preparations developing locomotor-like activity was as follows: 5-HT (43%), 5-HT/N-methyl-D-aspartate (NMDA; 33%), quipazine (42%), 8-hydroxy-2-(di-n-propylamino)tetralin (20%), methoxamine (45%), and elevated bath K(+) concentration (29%). Combined norepinephrine and dopamine increased the success rate (67%) compared with the use of either agent alone (4 and 7%, respectively). NMDA, Mg(2+) ion removal, clonidine, and acetylcholine were ineffective. The results provide proof of principle that artificial excitation of thoracic propriospinal neurons can improve supraspinal control over hindlimb locomotor networks in the lesioned spinal cord.

Help, I need to develop communication skills on donation: the "VIDEO" model.

PubMed

Smudla, A; Mihály, S; Hegedüs, K; Nemes, B; Fazakas, J

2011-05-01

Information about brain stem death and donation can be influence the consent rate for donation and its psychosocial effects. The aim of this study was to create a "VIDEO" model that could be used to help physicians to develop communication skills. A video recorded 32 simulations of family interviews: 16 under-age and 16 adult donors. They were analyzed during 8 courses conducted in 2008 and 2009. During the VIDEO process, the visual presentation was followed by participants (n=192) discussing interactively the donation situation. After the transcription of the video records, family interviews were explored retrospectively regarding informing relatives about brain stem death and donation, typical communication gaps and common questions from families. The data were examined qualitatively and semiquantitatively. We think that teaching can be optimized by our results. A comprehensible explanation about brain stem death was provided to relatives in 65.63% of cases. The consent of the family was more important for the physicians than the application of the law in 93.75%; 78.13% of physicians emphasized altruism to support donation. Remarkable mistakes of communication included using the teams coma and brain stem death interchangeably (9.38%); applying expressions connected with life in the present tense (21.88%) and mechanically kept alive (21.88%); organ-focused behavior such as "organs to be usable" (34.38%). The frequent questions and statements of "relatives" were "heart beats" (100%), "did he really die?" (65.63%), "fear of loss of integrity of the corpse" (59.38%), and "wake up from the coma" (46.88%). Interaction with the family requires great preparation. The communication skills of physicians can be developed through the VIDEO model. The results can be integrated into educational programs that consider the particular features of the given country. Copyright © 2011 Elsevier Inc. All rights reserved.

EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties.

PubMed

Miao, H; Gale, N W; Guo, H; Qian, J; Petty, A; Kaspar, J; Murphy, A J; Valenzuela, D M; Yancopoulos, G; Hambardzumyan, D; Lathia, J D; Rich, J N; Lee, J; Wang, B

2015-01-29

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma multiforme (GBM), but the underlying mechanisms remain incompletely understood. Using human glioma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild-type (WT) littermates. Mechanistically EphA2 knockdown suppressed stem cell properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem cell properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem cell properties in a kinase-independent manner and increased Sox2 expression. Disruption of Akt-EphA2 cross-talk attenuated stem cell marker expression and neurosphere formation while having minimal effects on tumorigenesis. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and regulates glioma stem cell properties.

Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage

PubMed Central

Roll, Lars; Faissner, Andreas

2014-01-01

The limited regeneration capacity of the adult central nervous system (CNS) requires strategies to improve recovery of patients. In this context, the interaction of endogenous as well as transplanted stem cells with their environment is crucial. An understanding of the molecular mechanisms could help to improve regeneration by targeted manipulation. In the course of reactive gliosis, astrocytes upregulate Glial fibrillary acidic protein (GFAP) and start, in many cases, to proliferate. Beside GFAP, subpopulations of these astroglial cells coexpress neural progenitor markers like Nestin. Although cells express these markers, the proportion of cells that eventually give rise to neurons is limited in many cases in vivo compared to the situation in vitro. In the first section, we present the characteristics of endogenous progenitor-like cells and discuss the differences in their neurogenic potential in vitro and in vivo. As the environment plays an important role for survival, proliferation, migration, and other processes, the second section of the review describes changes in the extracellular matrix (ECM), a complex network that contains numerous signaling molecules. It appears that signals in the damaged CNS lead to an activation and de-differentiation of astrocytes, but do not effectively promote neuronal differentiation of these cells. Factors that influence stem cells during development are upregulated in the damaged brain as part of an environment resembling a stem cell niche. We give a general description of the ECM composition, with focus on stem cell-associated factors like the glycoprotein Tenascin-C (TN-C). Stem cell transplantation is considered as potential treatment strategy. Interaction of transplanted stem cells with the host environment is critical for the outcome of stem cell-based therapies. Possible mechanisms involving the ECM by which transplanted stem cells might improve recovery are discussed in the last section. PMID:25191223

Investigation of the expression of RIF1 gene on head and neck, pancreatic and brain cancer and cancer stem cells.

PubMed

GursesCila, Hacer E; Acar, Muradiye; Barut, Furkan B; Gunduz, Mehmet; Grenman, Reidar; Gunduz, Esra

2016-12-01

Recent studies have shown that cancer stem cells are resistant to chemotherapy. The aim of this study was to compare RIF1 gene expression in head and neck, pancreatic cancer and glioma cell lines and the cancer stem cells isolated from these cell lines. UT-SCC-74 from Turku University and UT-SCC-74B primary tumor metastasis and neck cancer cell lines, YKG-1 glioma cancer cell line from RIKEN, pancreatic cancer cell lines and ASPC-1 cells from ATCC were grown in cell culture. To isolate cancer stem cells, ALDH-1 for UT-SCC-74 and UT-SCC-74B cell line, CD-133 for YKG-1 cell line and CD-24 for ASPC-1 cell line, were used as markers of cancer stem cells. RNA isolation was performed for both cancer lines and cancer stem cells. RNAs were converted to cDNA. RIF1 gene expression was performed by qRT-PCR analysis. RIF1 gene expression was compared with cancer cell lines and cancer stem cells isolated from these cell lines. The possible effect of RIF1 gene was evaluated. In the pancreatic cells, RIF1 gene expression in the stem cell-positive cell line was 256 time that seen in the stem cell-negative cell line. Considering the importance of RIF1 in NHEJ and of NHEJ in pancreatic cancer, RIF1 may be one of the genes that plays an important role in the diagnoses and therapeutic treatment of pancreatic cancer. The results of head and neck and brain cancers are inconclusive and further studies are required to elucidate the connection between RIF1 gene and these other types of cancers.

Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study.

PubMed

El Baz, Hanan; Demerdash, Zeinab; Kamel, Manal; Atta, Shimaa; Salah, Faten; Hassan, Salwa; Hammam, Olfat; Khalil, Heba; Meshaal, Safa; Raafat, Inas

2018-02-01

Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group.

In vivo differentiation of induced pluripotent stem cells into neural stem cells by chimera formation.

PubMed

Choi, Hyun Woo; Hong, Yean Ju; Kim, Jong Soo; Song, Hyuk; Cho, Ssang Gu; Bae, Hojae; Kim, Changsung; Byun, Sung June; Do, Jeong Tae

2017-01-01

Like embryonic stem cells, induced pluripotent stem cells (iPSCs) can differentiate into all three germ layers in an in vitro system. Here, we developed a new technology for obtaining neural stem cells (NSCs) from iPSCs through chimera formation, in an in vivo environment. iPSCs contributed to the neural lineage in the chimera, which could be efficiently purified and directly cultured as NSCs in vitro. The iPSC-derived, in vivo-differentiated NSCs expressed NSC markers, and their gene-expression pattern more closely resembled that of fetal brain-derived NSCs than in vitro-differentiated NSCs. This system could be applied for differentiating pluripotent stem cells into specialized cell types whose differentiation protocols are not well established.

Multifunctional nanomaterials for advanced molecular imaging and cancer therapy

NASA Astrophysics Data System (ADS)

Subramaniam, Prasad

Nanotechnology offers tremendous potential for use in biomedical applications, including cancer and stem cell imaging, disease diagnosis and drug delivery. The development of nanosystems has aided in understanding the molecular mechanisms of many diseases and permitted the controlled nanoscale manipulation of biological phenomena. In recent years, many studies have focused on the use of several kinds of nanomaterials for cancer and stem cell imaging and also for the delivery of anticancer therapeutics to tumor cells. However, the proper diagnosis and treatment of aggressive tumors such as brain and breast cancer requires highly sensitive diagnostic agents, in addition to the ability to deliver multiple therapeutics using a single platform to the target cells. Addressing these challenges, novel multifunctional nanomaterial-based platforms that incorporate multiple therapeutic and diagnostic agents, with superior molecular imaging and targeting capabilities, has been presented in this work. The initial part of this work presents the development of novel nanomaterials with superior optical properties for efficiently delivering soluble cues such as small interfering RNA (siRNA) into brain cancer cells with minimal toxicity. Specifically, this section details the development of non-toxic quantums dots for the imaging and delivery of siRNA into brain cancer and mesenchymal stem cells, with the hope of using these quantum dots as multiplexed imaging and delivery vehicles. The use of these quantum dots could overcome the toxicity issues associated with the use of conventional quantum dots, enabled the imaging of brain cancer and stem cells with high efficiency and allowed for the delivery of siRNA to knockdown the target oncogene in brain cancer cells. The latter part of this thesis details the development of nanomaterial-based drug delivery platforms for the co-delivery of multiple anticancer drugs to brain tumor cells. In particular, this part of the thesis focuses on the synthesis and use of a biodegradable dendritic polypeptide-based nanocarrier for the delivery of multiple anticancer drugs and siRNA to brain tumor cells. The co-delivery of important anticancer agents using a single platform was shown to increase the efficacy of the drugs manyfold, ensuring the cancer cell-specific delivery and minimizing dose limiting toxicities of the individual drugs. This would be of immense importance when used in vivo.

Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury.

PubMed

Llorens-Bobadilla, Enric; Zhao, Sheng; Baser, Avni; Saiz-Castro, Gonzalo; Zwadlo, Klara; Martin-Villalba, Ana

2015-09-03

Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Copyright © 2015 Elsevier Inc. All rights reserved.

Induction of brain tumor stem cell apoptosis by FTY720: a potential therapeutic agent for glioblastoma.

PubMed

Estrada-Bernal, Adriana; Palanichamy, Kamalakannan; Ray Chaudhury, Abhik; Van Brocklyn, James R

2012-04-01

FTY720 is a sphingosine analogue that down regulates expression of sphingosine-1-phosphate receptors and causes apoptosis of multiple tumor cell types, including glioma cells. This study examined the effect of FTY720 on brain tumor stem cells (BTSCs) derived from human glioblastoma (GBM) tissue. FTY720 treatment of BTSCs led to rapid inactivation of ERK MAP kinase, leading to upregulation of the BH3-only protein Bim and apoptosis. In combination with temozolomide (TMZ), the current standard chemotherapeutic agent for GBM, FTY720 synergistically induced BTSC apoptosis. FTY720 also slowed growth of intracranial xenograft tumors in nude mice and augmented the therapeutic effect of TMZ, leading to enhanced survival. Furthermore, the combination of FTY720 and TMZ decreased the invasiveness of BTSCs in mouse brains. FTY720 is known to cross the blood-brain barrier and recently received Food and Drug Administration approval for treatment of relapsing multiple sclerosis. Thus, FTY720 is an excellent potential therapeutic agent for treatment of GBM.

IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain.

PubMed

Bhattarai, Prabesh; Thomas, Alvin Kuriakose; Cosacak, Mehmet Ilyas; Papadimitriou, Christos; Mashkaryan, Violeta; Froc, Cynthia; Reinhardt, Susanne; Kurth, Thomas; Dahl, Andreas; Zhang, Yixin; Kizil, Caghan

2016-10-18

Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Differentiation and characterization of human pluripotent stem cell-derived brain microvascular endothelial cells.

PubMed

Stebbins, Matthew J; Wilson, Hannah K; Canfield, Scott G; Qian, Tongcheng; Palecek, Sean P; Shusta, Eric V

2016-05-15

The blood-brain barrier (BBB) is a critical component of the central nervous system (CNS) that regulates the flux of material between the blood and the brain. Because of its barrier properties, the BBB creates a bottleneck to CNS drug delivery. Human in vitro BBB models offer a potential tool to screen pharmaceutical libraries for CNS penetration as well as for BBB modulators in development and disease, yet primary and immortalized models respectively lack scalability and robust phenotypes. Recently, in vitro BBB models derived from human pluripotent stem cells (hPSCs) have helped overcome these challenges by providing a scalable and renewable source of human brain microvascular endothelial cells (BMECs). We have demonstrated that hPSC-derived BMECs exhibit robust structural and functional characteristics reminiscent of the in vivo BBB. Here, we provide a detailed description of the methods required to differentiate and functionally characterize hPSC-derived BMECs to facilitate their widespread use in downstream applications. Copyright © 2015 Elsevier Inc. All rights reserved.

Mesenchymal Stem Cells Regulate Blood Brain Barrier Integrity in Traumatic Brain Injury Through Production of the Soluble Factor TIMP3

PubMed Central

Menge, Tyler; Zhao, Yuhai; Zhao, Jing; Wataha, Kathryn; Geber, Michael; Zhang, Jianhu; Letourneau, Phillip; Redell, John; Shen, Li; Wang, Jing; Peng, Zhalong; Xue, Hasen; Kozar, Rosemary; Cox, Charles S.; Khakoo, Aarif Y.; Holcomb, John B.; Dash, Pramod K.; Pati, Shibani

2013-01-01

Mesenchymal stem cells (MCSs) have been shown to have therapeutic potential in multiple disease states associated with vascular instability including traumatic brain injury (TBI). In the present study, Tissue Inhibitor of Matrix Metalloproteinase-3 (TIMP3) is identified as the soluble factor produced by MSCs that can recapitulate the beneficial effects of MSCs on endothelial function and blood brain barrier (BBB) compromise in TBI. Attenuation of TIMP3 expression in MSCs completely abrogates the effect of MSCs on BBB permeability and stability, while intravenous administration of rTIMP3 alone can inhibit BBB permeability in TBI. Our results demonstrate that MSCs increase circulating levels of soluble TIMP3, which inhibits VEGF-A induced breakdown of endothelial AJs in vitro and in vivo. These findings elucidate a clear molecular mechanism for the effects of MSCs on the BBB in TBI, and directly demonstrate a role for TIMP3 in regulation of BBB integrity. PMID:23175708

Outbreaks of Neuroinvasive Astrovirus Associated with Encephalomyelitis, Weakness, and Paralysis among Weaned Pigs, Hungary

PubMed Central

Boros, Ákos; Albert, Mihály; Pankovics, Péter; Bíró, Hunor; Pesavento, Patricia A.; Phan, Tung Gia; Delwart, Eric

2017-01-01

A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease. PMID:29148391

Outbreaks of Neuroinvasive Astrovirus Associated with Encephalomyelitis, Weakness, and Paralysis among Weaned Pigs, Hungary.

PubMed

Boros, Ákos; Albert, Mihály; Pankovics, Péter; Bíró, Hunor; Pesavento, Patricia A; Phan, Tung Gia; Delwart, Eric; Reuter, Gábor

2017-12-01

A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease.

Anxiety and the aging brain: stressed out over p53?

PubMed

Scrable, Heidi; Burns-Cusato, Melissa; Medrano, Silvia

2009-12-01

We propose a model in which cell loss in the aging brain is seen as a root cause of behavioral changes that compromise quality of life, including the onset of generalized anxiety disorder, in elderly individuals. According to this model, as stem cells in neurogenic regions of the adult brain lose regenerative capacity, worn-out, dead, or damaged neurons fail to be replaced, leaving gaps in function. As most replacement involves inhibitory interneurons, either directly or indirectly, the net result is the acquisition over time of a hyper-excitable state. The stress axis is subserved by all three neurogenic regions in the adult brain, making it particularly susceptible to these age-dependent changes. We outline a molecular mechanism by which hyper-excitation of the stress axis in turn activates the tumor suppressor p53. This reinforces the loss of stem cell proliferative capacity and interferes with the feedback mechanism by which the glucocorticoid receptor turns off neuroendocrine pathways and resets the axis.

Quantitative Evaluation of Brain Stem Atrophy Using Magnetic Resonance Imaging in Adult Patients with Alexander Disease.

PubMed

Yoshida, Tomokatsu; Yasuda, Rei; Mizuta, Ikuko; Nakagawa, Masanori; Mizuno, Toshiki

2017-01-01

Brain MRI in adult patients with Alexander disease (AxD) mainly shows atrophy in the medulla oblongata. However, currently there is no quantitative standard for assessing this atrophy. In this study, we quantitatively evaluated the brain stem of AxD patients with glial fibrillary acidic protein (GFAP) mutation using conventional MRI to evaluate its usefulness as an aid to diagnosing AxD in daily clinical practice. Nineteen AxD patients with GFAP mutation were compared with 14 patients negative for GFAP mutation in whom AxD was suspected due to "atrophy of the medulla oblongata." In the GFAP mutation-positive group, the sagittal diameter of the medulla oblongata, the ratio of the diameter of the medulla oblongata to that of the midbrain (MO/MB), and the ratio of the sagittal diameter of the medulla oblongata to that of the pons (MO/Po) were significantly smaller compared to those of the GFAP mutation-negative group (p < 0.01). The sensitivity and specificity of each parameter were 87.5 and 92.3%, 91.7 and 81.3%, and 88.2 and 100% with a sagittal diameter of the medulla oblongata <9.0 mm, MO/MB <0.60, and sagittal MO/Po <0.46, respectively. These parameters can provide very useful information to differentially diagnose AxD from other disorders associated with brain stem atrophy in adult patients. © 2017 S. Karger AG, Basel.

Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells.

PubMed

Al-Ahmad, Abraham J

2017-10-01

Glucose constitutes a major source of energy of mammalian brains. Glucose uptake at the blood-brain barrier (BBB) occurs through a facilitated glucose transport, through glucose transporter 1 (GLUT1), although other isoforms have been described at the BBB. Mutations in GLUT1 are associated with the GLUT1 deficiency syndrome, yet none of the current in vitro models of the human BBB maybe suited for modeling such a disorder. In this study, we investigated the expression of glucose transporters and glucose diffusion across brain microvascular endothelial cells (BMECs) derived from healthy patient-derived induced pluripotent stem cells (iPSCs). We investigated the expression of different glucose transporters at the BBB using immunocytochemistry and flow cytometry and measured glucose uptake and diffusion across BMEC monolayers obtained from two iPSC lines and from hCMEC/D3 cells. BMEC monolayers showed expression of several glucose transporters, in particular GLUT1, GLUT3, and GLUT4. Diffusion of glucose across the monolayers was mediated via a saturable transcellular mechanism and partially inhibited by pharmacological inhibitors. Taken together, our study suggests the presence of several glucose transporters isoforms at the human BBB and demonstrates the feasibility of modeling glucose across the BBB using patient-derived stem cells. Copyright © 2017 the American Physiological Society.

Brain mesenchymal stem cells: physiology and pathological implications.

PubMed

Pombero, Ana; Garcia-Lopez, Raquel; Martinez, Salvador

2016-06-01

Mesenchymal stem cells (MSCs) are defined as progenitor cells that give rise to a number of unique, differentiated mesenchymal cell types. This concept has progressively evolved towards an all-encompassing concept including multipotent perivascular cells of almost any tissue. In central nervous system, pericytes are involved in blood-brain barrier, and angiogenesis and vascular tone regulation. They form the neurovascular unit (NVU) together with endothelial cells, astrocytes and neurons. This functional structure provides an optimal microenvironment for neural proliferation in the adult brain. Neurovascular niche include both diffusible signals and direct contact with endothelial and pericytes, which are a source of diffusible neurotrophic signals that affect neural precursors. Therefore, MSCs/pericyte properties such as differentiation capability, as well as immunoregulatory and paracrine effects make them a potential resource in regenerative medicine. © 2016 Japanese Society of Developmental Biologists.

Student Global Mobility: An Analysis of International STEM Student Brain Drain

ERIC Educational Resources Information Center

Gesing, Margaret E.

2017-01-01

This study seeks to understand global mobility patterns of international graduate STEM students studying in the United States. Using data from the NSF Graduate Students in Science Survey (GSSS), this study investigates the political, economic, and social factors affecting students' intent to stay or go, identifying differences based on students'…

Fostering Creativity and Innovation through Technology

ERIC Educational Resources Information Center

Vaidyanathan, Sheena

2012-01-01

To compete in the global workforce, educators know that their students must be well educated in science, engineering, technology, and mathematics (STEM) subjects. But, as outlined in the NETS, they must also develop the key skills of creativity and innovation. How can educators teach the typically left-brained STEM subjects along with the more…

Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles

PubMed Central

Hu, Chenxia; Niestroj, Martin; Yuan, Daniel; Chang, Steven; Chen, Jie

2015-01-01

Cancer ranks among the leading causes of human mortality. Cancer becomes intractable when it spreads from the primary tumor site to various organs (such as bone, lung, liver, and then brain). Unlike solid tumor cells, cancer stem cells and metastatic cancer cells grow in a non-attached (suspension) form when moving from their source to other locations in the body. Due to the non-attached growth nature, metastasis is often first detected in the circulatory systems, for instance in a lymph node near the primary tumor. Cancer research over the past several decades has primarily focused on treating solid tumors, but targeted therapy to treat cancer stem cells and cancer metastasis has yet to be developed. Because cancers undergo faster metabolism and consume more glucose than normal cells, glucose was chosen in this study as a reagent to target cancer cells. In particular, by covalently binding gold nanoparticles (GNPs) with thio-PEG (polyethylene glycol) and thio-glucose, the resulting functionalized GNPs (Glu-GNPs) were created for targeted treatment of cancer metastasis and cancer stem cells. Suspension cancer cell THP-1 (human monocytic cell line derived from acute monocytic leukemia patients) was selected because it has properties similar to cancer stem cells and has been used as a metastatic cancer cell model for in vitro studies. To take advantage of cancer cells’ elevated glucose consumption over normal cells, different starvation periods were screened in order to achieve optimal treatment effects. Cancer cells were then fed using Glu-GNPs followed by X-ray irradiation treatment. For comparison, solid tumor MCF-7 cells (breast cancer cell line) were studied as well. Our irradiation experimental results show that Glu-GNPs are better irradiation sensitizers to treat THP-1 cells than MCF-7 cells, or Glu-GNPs enhance the cancer killing of THP-1 cells 20% more than X-ray irradiation alone and GNP treatment alone. This finding can help oncologists to design therapeutic strategies to target cancer stem cells and cancer metastasis. PMID:25844037

Induced neural stem cells achieve long-term survival and functional integration in the adult mouse brain.

PubMed

Hemmer, Kathrin; Zhang, Mingyue; van Wüllen, Thea; Sakalem, Marna; Tapia, Natalia; Baumuratov, Aidos; Kaltschmidt, Christian; Kaltschmidt, Barbara; Schöler, Hans R; Zhang, Weiqi; Schwamborn, Jens C

2014-09-09

Differentiated cells can be converted directly into multipotent neural stem cells (i.e., induced neural stem cells [iNSCs]). iNSCs offer an attractive alternative to induced pluripotent stem cell (iPSC) technology with regard to regenerative therapies. Here, we show an in vivo long-term analysis of transplanted iNSCs in the adult mouse brain. iNSCs showed sound in vivo long-term survival rates without graft overgrowths. The cells displayed a neural multilineage potential with a clear bias toward astrocytes and a permanent downregulation of progenitor and cell-cycle markers, indicating that iNSCs are not predisposed to tumor formation. Furthermore, the formation of synaptic connections as well as neuronal and glial electrophysiological properties demonstrated that differentiated iNSCs migrated, functionally integrated, and interacted with the existing neuronal circuitry. We conclude that iNSC long-term transplantation is a safe procedure; moreover, it might represent an interesting tool for future personalized regenerative applications. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

The Manpower Quality Decline: An Ecological Perspective

DTIC Science & Technology

1981-01-01

90 These factors can influence the human brain prenatally as well as during childhood and adolescence. In some cases, the ecological effects appear...decerebrate (as though they had no cerebral cortex) rigidity following application of 6 percent hexachlorophene powder. Examina- tion of brain stems of...correlation between hexachlorophene baths and lesions in white matter of brains .... Phisohex should not be used routinely for bathing infants. The 1976

Orchestrating brain-cell renewal: the role of immune cells in adult neurogenesis in health and disease.

PubMed

Ziv, Yaniv; Schwartz, Michal

2008-11-01

Immune cells and immune molecules have recently been shown to support neurogenesis from neural stem and progenitor cells in the adult brain. This non-classical immune activity takes place constantly under normal physiological conditions and is extended under acute pathological conditions to include the attraction of progenitor cells and induction of neurogenesis in regions of the adult central nervous system (CNS) in which formation of new neurons does not normally occur. We suggest that the immune system should be viewed as a novel player in the adult neural stem cell niche and a coordinator of cell renewal processes after injury. We discuss these notions in light of the well-known facts that both immune-cell activity and cell renewal are inherently limited in the adult CNS and that immune and stem cells provide the body's mechanisms of repair.

p53 is required for brain growth but is dispensable for resistance to nutrient restriction during Drosophila larval development

PubMed Central

Contreras, Esteban G.; Sierralta, Jimena

2018-01-01

Background Animal growth is influenced by the genetic background and the environmental circumstances. How genes promote growth and coordinate adaptation to nutrient availability is still an open question. p53 is a transcription factor that commands the cellular response to different types of stresses. In adult Drosophila melanogaster, p53 regulates the metabolic adaptation to nutrient restriction that supports fly viability. Furthermore, the larval brain is protected from nutrient restriction in a phenomenon called ‘brain sparing’. Therefore, we hypothesised that p53 may regulate brain growth and show a protective role over brain development under nutrient restriction. Results Here, we studied the function of p53 during brain growth in normal conditions and in animals subjected to developmental nutrient restriction. We showed that p53 loss of function reduced animal growth and larval brain size. Endogenous p53 was expressed in larval neural stem cells, but its levels and activity were not affected by nutritional stress. Interestingly, p53 knockdown only in neural stem cells was sufficient to decrease larval brain growth. Finally, we showed that in p53 mutant larvae under nutrient restriction, the energy storage levels were not altered, and these larvae generated adults with brains of similar size than wild-type animals. Conclusions Using genetic approaches, we demonstrate that p53 is required for proper growth of the larval brain. This developmental role of p53 does not have an impact on animal resistance to nutritional stress since brain growth in p53 mutants under nutrient restriction is similar to control animals. PMID:29621246

p53 is required for brain growth but is dispensable for resistance to nutrient restriction during Drosophila larval development.

PubMed

Contreras, Esteban G; Sierralta, Jimena; Glavic, Alvaro

2018-01-01

Animal growth is influenced by the genetic background and the environmental circumstances. How genes promote growth and coordinate adaptation to nutrient availability is still an open question. p53 is a transcription factor that commands the cellular response to different types of stresses. In adult Drosophila melanogaster, p53 regulates the metabolic adaptation to nutrient restriction that supports fly viability. Furthermore, the larval brain is protected from nutrient restriction in a phenomenon called 'brain sparing'. Therefore, we hypothesised that p53 may regulate brain growth and show a protective role over brain development under nutrient restriction. Here, we studied the function of p53 during brain growth in normal conditions and in animals subjected to developmental nutrient restriction. We showed that p53 loss of function reduced animal growth and larval brain size. Endogenous p53 was expressed in larval neural stem cells, but its levels and activity were not affected by nutritional stress. Interestingly, p53 knockdown only in neural stem cells was sufficient to decrease larval brain growth. Finally, we showed that in p53 mutant larvae under nutrient restriction, the energy storage levels were not altered, and these larvae generated adults with brains of similar size than wild-type animals. Using genetic approaches, we demonstrate that p53 is required for proper growth of the larval brain. This developmental role of p53 does not have an impact on animal resistance to nutritional stress since brain growth in p53 mutants under nutrient restriction is similar to control animals.

Preparing neural stem/progenitor cells in PuraMatrix hydrogel for transplantation after brain injury in rats: A comparative methodological study.

PubMed

Aligholi, Hadi; Rezayat, Seyed Mahdi; Azari, Hassan; Ejtemaei Mehr, Shahram; Akbari, Mohammad; Modarres Mousavi, Seyed Mostafa; Attari, Fatemeh; Alipour, Fatemeh; Hassanzadeh, Gholamreza; Gorji, Ali

2016-07-01

Cultivation of neural stem/progenitor cells (NS/PCs) in PuraMatrix (PM) hydrogel is an option for stem cell transplantation. The efficacy of a novel method for placing adult rat NS/PCs in PM (injection method) was compared to encapsulation and surface plating approaches. In addition, the efficacy of injection method for transplantation of autologous NS/PCs was studied in a rat model of brain injury. NS/PCs were obtained from the subventricular zone (SVZ) and cultivated without (control) or with scaffold (three-dimensional cultures; 3D). The effect of different approaches on survival, proliferation, and differentiation of NS/PCs were investigated. In in vivo study, brain injury was induced 45 days after NS/PCs were harvested from the SVZ and phosphate buffered saline, PM, NS/PCs, or PM+NS/PCs were injected into the brain lesion. There was an increase in cell viability and proliferation after injection and surface plating of NS/PCs compared to encapsulation and neural differentiation markers were expressed seven days after culturing the cells. Using injection method, transplantation of NS/PCs cultured in PM resulted in significant reduction of lesion volume, improvement of neurological deficits, and enhancement of surviving cells. In addition, the transplanted cells could differentiate in to neurons, astrocytes, or oligodendrocytes. Our results indicate that the injection and surface plating methods enhanced cell survival and proliferation of NS/PCs and suggest the injection method as a promising approach for transplantation of NS/PCs in brain injury. Copyright © 2016 Elsevier B.V. All rights reserved.

Hepatocyte growth factor/c-MET axis-mediated tropism of cord blood-derived unrestricted somatic stem cells for neuronal injury.

PubMed

Trapp, Thorsten; Kögler, Gesine; El-Khattouti, Abdelouahid; Sorg, Rüdiger V; Besselmann, Michael; Föcking, Melanie; Bührle, Christian P; Trompeter, Ingo; Fischer, Johannes C; Wernet, Peter

2008-11-21

An under-agarose chemotaxis assay was used to investigate whether unrestricted somatic stem cells (USSC) that were recently characterized in human cord blood are attracted by neuronal injury in vitro. USSC migrated toward extracts of post-ischemic brain tissue of mice in which stroke had been induced. Moreover, apoptotic neurons secrete factors that strongly attracted USSC, whereas necrotic and healthy neurons did not. Investigating the expression of growth factors and chemokines in lesioned brain tissue and neurons and of their respective receptors in USSC revealed expression of hepatocyte growth factor (HGF) in post-ischemic brain and in apoptotic but not in necrotic neurons and of the HGF receptor c-MET in USSC. Neuronal lesion-triggered migration was observed in vitro and in vivo only when c-MET was expressed at a high level in USSC. Neutralization of the bioactivity of HGF with an antibody inhibited migration of USSC toward neuronal injury. This, together with the finding that human recombinant HGF attracts USSC, document that HGF signaling is necessary for the tropism of USSC for neuronal injury. Our data demonstrate that USSC have the capacity to migrate toward apoptotic neurons and injured brain. Together with their neural differentiation potential, this suggests a neuroregenerative potential of USSC. Moreover, we provide evidence for a hitherto unrecognized pivotal role of the HGF/c-MET axis in guiding stem cells toward brain injury, which may partly account for the capability of HGF to improve function in the diseased central nervous system.

Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice

PubMed Central

Barzilay, R; Ben-Zur, T; Sadan, O; Bren, Z; Taler, M; Lev, N; Tarasenko, I; Uzan, R; Gil-Ad, I; Melamed, E; Weizman, A; Offen, D

2011-01-01

Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson's and Huntington's diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre-frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg−1 daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs-treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder. PMID:22832353

Magnetic resonance imaging of the pediatric brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salamon, G.; Raynaud, C.; Regis, J.

1990-01-01

The atlas presents sequences of MRI sections parallel to the orbito-meatal plane in children from birth through the age of sixteen years. Each child was studied horizontally and sagitally and three-dimensional brain images were reconstructed to facilitate accurate identification of sulci and gyri. The images show crucial aspects of brain development such as the constancy of the brain stem and primitive brain from birth onward; the development of the telencephalon, characterized by deepening of sulci and growth of the cerebral cortex surface; and the different stages of white matter myelinization.

Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function

USDA-ARS?s Scientific Manuscript database

Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plas...

Serial computed tomography and magnetic resonance imaging findings of biphasic acute hemorrhagic leukoencephalitis localized to the brain stem and cerebellum.

PubMed

Lee, Nyoung Keun; Lee, Byung Hoon; Hwang, Yoon Joon; Kim, Su Young; Lee, Ji Young; Joo, Mee

2011-04-01

Acute hemorrhagic leukoencephalitis (AHL) is a rare and usually fatal disease characterized by an acute onset of neurological abnormalities. We describe the case of a 37-year-old man with biphasic AHL with a focus on the rare involvement of the brain stem and cerebellum. Initial computed tomography (CT) and magnetic resonance imaging revealed two hemorrhagic foci in the left middle cerebellar peduncle. After 15 days multifocal hematomas in the contralateral cerebellar hemisphere were imaged using CT. The pathological diagnosis was AHL. Following high-dose steroid treatment, the patient recovered with minor neurological sequelae.

Anticholinesterase activities of cold and hot aqueous extracts of F. racemosa stem bark.

PubMed

Ahmed, Faiyaz; Urooj, Asna

2010-04-01

The present study evaluated the anticholinesterase activity of cold and hot aqueous extracts of Ficus racemosa stem bark against rat brain acetylcholinesterase in vitro. Both the cold aqueous extract (FRC) and the hot aqueous extract (FRH) exhibited a dose dependent inhibition of rat brain acetylcholinesterase. FRH showed significantly higher (P

St. Louis Encephalitis in Children

PubMed Central

Kaplan, Allen M.; Longhurst, William L.; Randall, Donald L.

1978-01-01

St. Louis encephalitis is not an uncommon cause of seasonal meningoencephalitis in children. The clinical presentation is variable and may range from inapparent infection to a severe illness with diverse neurologic signs. A review of three recent cases of St. Louis encephalitis in children in Phoenix, Arizona, stresses the need to consider this type of encephalitis in patients with signs of brain stem dysfunction or acute cerebellar ataxia. The appearance of these clinical signs is supported by the pathologic changes that have been documented to occur, most frequently in the thalamus and brain stem. The importance of serologic identification to facilitate early vector control is emphasized. PMID:664627

Brain-stem evoked potentials and noise effects in seagulls.

PubMed

Counter, S A

1985-01-01

Brain-stem auditory evoked potentials (BAEP) recorded from the seagull were large-amplitude, short-latency, vertex-positive deflections which originate in the eighth nerve and several brain-stem nuclei. BAEP waveforms were similar in latency and configurations to that reported for certain other lower vertebrates and some mammals. BAEP recorded at several pure tone frequencies throughout the seagull's auditory spectrum showed an area of heightened auditory sensitivity between 1 and 3 kHz. This range was also found to be the primary bandwidth of the vocalization output of young seagulls. Masking by white noise and pure tones had remarkable effects on several parameters of the BAEP. In general, the tone- and click-induced BAEP were either reduced or obliterated by both pure tone and white noise maskers of specific signal to noise ratios and high intensity levels. The masking effects observed in this study may be related to the manner in which seagulls respond to intense environmental noise. One possible conclusion is that intense environmental noise, such as aircraft engine noise, may severely alter the seagull's localization apparatus and induce sonogenic stress, both of which could cause collisions with low-flying aircraft.

Effective treatment of glioblastoma requires crossing the blood–brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine

PubMed Central

Kim, Sang-Soo; Harford, Joe B.; Pirollo, Kathleen F.; Chang, Esther H.

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood–brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. PMID:26116770

Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys.

PubMed

Ayajiki, Kazuhide; Kobuchi, Shuhei; Tawa, Masashi; Okamura, Tomio

2012-01-01

The functional roles of the nitrergic nerves innervating the monkey cerebral artery were evaluated in a tension-response study examining isolated arteries in vitro and cerebral angiography in vivo. Nicotine produced relaxation of arteries by stimulation of nerve terminals innervating isolated monkey arteries irrigating the cerebrum, cerebellum and brain stem. Relaxation of arteries induced by nicotine was abolished by treatment with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, and was restored by addition of L-arginine. Cerebral angiography showed that electrical stimulation of the unilateral greater petrosal nerve, which connects to the pterygopalatine ganglion via the parasympathetic ganglion synapse, produced vasodilatation of the anterior, middle and posterior cerebral arteries in the stimulated side. However, stimulation failed to produce vasodilatation of the superior and anterior-inferior cerebellar arteries and the basilar artery in anesthetized monkeys. Therefore, nitrergic nerves derived from the pterygopalatine ganglion appear to regulate cerebral vasomotor function. In contrast, circulation in the cerebellum and brain stem might be regulated by nitrergic nerves originating not from the pterygopalatine ganglion, but rather from an unknown ganglion (or ganglia).

Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location.

PubMed

Joseph, Jeena; Behari, Sanjay; Gupta, Shruti; Bhaisora, Kamlesh Singh; Gandhi, Anish; Srivastava, Arun; Jaiswal, Awadhesh K

2018-01-01

Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 ± 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto-mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow-up visit (median: 25 ± interquartile range 2-56months), 17 patients had improved KPS, 4 remained in same status and 3 (recently operated, on tracheostomy) had worsened KPS. Significant improvement is achievable in neurological status in patients following successful extirpation of a brain-stem hemangioblastoma, despite a turbulent perioperative period. Leaving tumour capsule adherent to the brain-stem often helps in preserving brain-stem function. Postoperatively, the patients should be monitored for their respiratory and lower cranial nerve status to prevent aspiration pneumonitis.

[Stereotactic biopsy in the accurate diagnosis of lesions in the brain stem and deep brain].

PubMed

Qin, F; Huang, Z C; Cai, M Q; Xu, X F; Lu, T T; Dong, Q; Wu, A M; Lu, Z Z; Zhao, C; Guo, Y

2018-06-12

Objective: To investigate the value of stereotactic biopsy in the accurate diagnosis of lesions in the brain stem and deep brain. Methods: A total of 29 consecutive patients who underwent stereotactic biopsy of brainstem and deep brain lesions between May 2012 and January 2018 were retrospectively reviewed. The Cosman-Roberts-Wells (CRW) stereotactic frame was installed under local anesthesia. Thin-layer CT and MRI scanning were performed. Target coordinates were calculated by inputting CT-MRI data into the radionics surgical planning system. The individualized puncture path was designed according to the location of the lesions and the characteristics of the image. Target distributions were as follows: 12 cases of midbrain or pons, 2 cases of internal capsule, 3 cases of thalamus, 12 cases of basal ganglia. The biopsy samples were used for further pathological and/or genetic diagnosis. Results: Twenty-eight of the 29 cases (96.6%) were diagnosed accurately by histopathology and genomic examination following stereotactic biopsy. Pathological results were as follows: 8 cases of lymphoma, 7 cases of glioma, 4 cases of demyelination, 2 cases of germ cell tumor, 2 cases of metastatic tumor, 1 cases of cerebral sparganosis, 1 case of tuberculous granuloma, 1 case of hereditary prion disease, 1 case of glial hyperplasia, 1 case of leukemia. The accurate diagnosis of one case required a combination of histopathology and genomic examination. Undefined diagnosis was still made in 1 cases (3.45%) after biopsy. After biopsy, there were 2 cases (6.9%) with symptomatic slight hemorrhage, 1 case (3.45%) with symptomatic severe hemorrhage, and 1 cass (3.45%) with permanent neurological dysfunction. No one died because of surgery or surgical complications. Conclusions: Stereotactic biopsy is fast, safe and minimally invasive. It is an ideal strategy for accurate diagnosis of lesions in brain stem and deep brain.

Production and characterization of immortal human neural stem cell line with multipotent differentiation property.

PubMed

Kim, Seung U; Nagai, Atsushi; Nakagawa, Eiji; Choi, Hyun B; Bang, Jung H; Lee, Hong J; Lee, Myung A; Lee, Yong B; Park, In H

2008-01-01

We document the protocols and methods for the production of immortalized cell lines of human neural stem cells from the human fetal central nervous system (CNS) cells by using a retroviral vector encoding v-myc oncogene. One of the human neural stem cell lines (HB1.F3) was found to express nestin and other specific markers for human neural stem cells, giving rise to three fundamental cell types of the CNS: neurons, astrocytes, and oligodendrocytes. After transplantation into the brain of mouse model of stroke, implanted human neural stem cells were observed to migrate extensively from the site of implantation into other anatomical sites and to differentiate into neurons and glial cells.

CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway

PubMed Central

Jijiwa, Mayumi; Demir, Habibe; Gupta, Snehalata; Leung, Crystal; Joshi, Kaushal; Orozco, Nicholas; Huang, Tiffany; Yildiz, Vedat O.; Shibahara, Ichiyo; de Jesus, Jason A.; Yong, William H.; Mischel, Paul S.; Fernandez, Soledad; Kornblum, Harley I.; Nakano, Ichiro

2011-01-01

Identification of stem cell-like brain tumor cells (brain tumor stem-like cells; BTSC) has gained substantial attention by scientists and physicians. However, the mechanism of tumor initiation and proliferation is still poorly understood. CD44 is a cell surface protein linked to tumorigenesis in various cancers. In particular, one of its variant isoforms, CD44v6, is associated with several cancer types. To date its expression and function in BTSC is yet to be identified. Here, we demonstrate the presence and function of the variant form 6 of CD44 (CD44v6) in BTSC of a subset of glioblastoma multiforme (GBM). Patients with CD44high GBM exhibited significantly poorer prognoses. Among various variant forms, CD44v6 was the only isoform that was detected in BTSC and its knockdown inhibited in vitro growth of BTSC from CD44high GBM but not from CD44low GBM. In contrast, this siRNA-mediated growth inhibition was not apparent in the matched GBM sample that does not possess stem-like properties. Stimulation with a CD44v6 ligand, osteopontin (OPN), increased expression of phosphorylated AKT in CD44high GBM, but not in CD44low GBM. Lastly, in a mouse spontaneous intracranial tumor model, CD44v6 was abundantly expressed by tumor precursors, in contrast to no detectable CD44v6 expression in normal neural precursors. Furthermore, overexpression of mouse CD44v6 or OPN, but not its dominant negative form, resulted in enhanced growth of the mouse tumor stem-like cells in vitro. Collectively, these data indicate that a subset of GBM expresses high CD44 in BTSC, and its growth may depend on CD44v6/AKTpathway. PMID:21915300

TOPICAL REVIEW: Stem cells engineering for cell-based therapy

NASA Astrophysics Data System (ADS)

Taupin, Philippe

2007-09-01

Stem cells carry the promise to cure a broad range of diseases and injuries, from diabetes, heart and muscular diseases, to neurological diseases, disorders and injuries. Significant progresses have been made in stem cell research over the past decade; the derivation of embryonic stem cells (ESCs) from human tissues, the development of cloning technology by somatic cell nuclear transfer (SCNT) and the confirmation that neurogenesis occurs in the adult mammalian brain and that neural stem cells (NSCs) reside in the adult central nervous system (CNS), including that of humans. Despite these advances, there may be decades before stem cell research will translate into therapy. Stem cell research is also subject to ethical and political debates, controversies and legislation, which slow its progress. Cell engineering has proven successful in bringing genetic research to therapy. In this review, I will review, in two examples, how investigators are applying cell engineering to stem cell biology to circumvent stem cells' ethical and political constraints and bolster stem cell research and therapy.

The Stem Cell Marker Lgr5 Defines a Subset of Postmitotic Neurons in the Olfactory Bulb.

PubMed

Yu, Yiqun; Moberly, Andrew H; Bhattarai, Janardhan P; Duan, Chen; Zheng, Qian; Li, Fangqi; Huang, Hugh; Olson, William; Luo, Wenqin; Wen, Tieqiao; Yu, Hongmeng; Ma, Minghong

2017-09-27

Lgr5, leucine-rich repeat-containing G-protein coupled receptor 5, is a bona fide biomarker for stem cells in multiple tissues. Lgr5 is also expressed in the brain, but the identities and properties of these Lgr5 + cells are still elusive. Using an Lgr5-EGFP reporter mouse line, we found that, from early development to adulthood, Lgr5 is highly expressed in the olfactory bulb (OB), an area with ongoing neurogenesis. Immunostaining with stem cell, glial, and neuronal markers reveals that Lgr5 does not label stem cells in the OB but instead labels a heterogeneous population of neurons with preference in certain subtypes. Patch-clamp recordings in OB slices reveal that Lgr5-EGFP + cells fire action potentials and display spontaneous excitatory postsynaptic events, indicating that these neurons are integrated into OB circuits. Interestingly, R-spondin 3, a potential ligand of Lgr5, is also expressed in the adult OB. Collectively, our data indicate that Lgr5-expressing cells in the OB are fully differentiated neurons and imply distinct roles of Lgr5 and its ligand in postmitotic cells. SIGNIFICANCE STATEMENT Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) is a bona fide stem cell marker in many body organs. Here we report that Lgr5 is also highly expressed in the olfactory bulb (OB), the first relay station in the brain for processing odor information and one of the few neural structures that undergo continuous neurogenesis. Surprisingly, Lgr5 is not expressed in the OB stem cells, but instead in a few subtypes of terminally differentiated neurons, which are incorporated into the OB circuit. This study reveals that Lgr5 + cells in the brain represent a nonstem cell lineage, implying distinct roles of Lgr5 in postmitotic neurons. Copyright © 2017 the authors 0270-6474/17/379403-12$15.00/0.

Adult neural stem cell cycling in vivo requires thyroid hormone and its alpha receptor.

PubMed

Lemkine, G F; Raj, A; Alfama, G; Turque, N; Hassani, Z; Alegria-Prévot, O; Samarut, J; Levi, G; Demeneix, B A

2005-05-01

Thyroid hormones (TH) are essential for brain development. However, information on if and how this key endocrine factor affects adult neurogenesis is fragmentary. We thus investigated the effects of TH on proliferation and apoptosis of stem cells in the subventricular zone (SVZ), as well as on migration of transgene-tagged neuroblasts out of the stem cell niche. Hypothyroidism significantly reduced all three of these processes, inhibiting generation of new cells. To determine the mechanisms relaying TH action in the SVZ, we analyzed which receptor was implicated and whether the effects were played out directly at the level of the stem cell population. The alpha TH receptor (TRalpha), but not TRbeta, was found to be expressed in nestin positive progenitor cells of the SVZ. Further, use of TRalpha mutant mice showed TRalpha to be required to maintain full proliferative activity. Finally, a direct TH transcriptional effect, not mediated through other cell populations, was revealed by targeted gene transfer to stem cells in vivo. Indeed, TH directly modulated transcription from the c-myc promoter reporter construct containing a functional TH response element containing TRE but not from a mutated TRE sequence. We conclude that liganded-TRalpha is critical for neurogenesis in the adult mammalian brain.

Atomic bonding effects in annular dark field scanning transmission electron microscopy. II. Experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Odlyzko, Michael L.; Held, Jacob T.; Mkhoyan, K. Andre, E-mail: mkhoyan@umn.edu

2016-07-15

Quantitatively calibrated annular dark field scanning transmission electron microscopy (ADF-STEM) imaging experiments were compared to frozen phonon multislice simulations adapted to include chemical bonding effects. Having carefully matched simulation parameters to experimental conditions, a depth-dependent bonding effect was observed for high-angle ADF-STEM imaging of aluminum nitride. This result is explained by computational predictions, systematically examined in the preceding portion of this study, showing the propagation of the converged STEM beam to be highly sensitive to net interatomic charge transfer. Thus, although uncertainties in experimental conditions and simulation accuracy remain, the computationally predicted experimental bonding effect withstands the experimental testing reportedmore » here.« less

Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas

ClinicalTrials.gov

2017-10-25

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

The diagnosis of organic brain syndrome.

PubMed

Berger, D M

1977-03-01

Because it stems from a variety of causes and interacting factors, organic brain syndrome is a difficult condition to diagnose. Several factors make it distinguishable from functional disorders, schizophrenia or hysteria. The syndrome cannot be considered in isolation from the patient's personality, however, since this will affect his coping with the disorder.

Neural Stem Cell Delivery of Therapeutic Antibodies to Treat Breast Cancer Brain Metastases

DTIC Science & Technology

2009-10-01

brain tumors remains dismal. High-grade neoplasms , such as gliomas, are highly invasive and spawn widely disseminated microsatellites that have... myeloproliferative sarcoma virus long terminal repeat negative control region deleted (MND promoter), allows suffi- cient expression in some cell types at a level

Relations between Neurological Aberrations and Psychological Dysfunctions in Children with Serious Language Problems.

ERIC Educational Resources Information Center

Bo, Ola O.; And Others

1992-01-01

Relationships between neuropsychological aberrations and psychological dysfunction were studied for 20 Swedish children (average age around 10 years at first testing) with serious language problems through (1) electroencephalography; (2) brain stem response audiometry; (3) magnetic resonance imaging; and (4) brain electric activity mapping by…

Changes in the brain biogenic monoamines of rats, induced by piracetam and aniracetam.

PubMed

Petkov, V D; Grahovska, T; Petkov, V V; Konstantinova, E; Stancheva, S

1984-01-01

Single oral dose of 600 mg/kg weight piracetam, respectively 50 mg/kg aniracetam, causes essential changes in the level and turnover of dopamine (DA) and serotonin (5-HT) in some rat cerebral structures. When the animals were killed one hour after the administration of the drugs, piracetam significantly increased the DA level in the cerebral cortex and in the striatum, as well as the 5-HT level in the cortex, reducing the 5-HT level in the striatum, brain stem and hypothalamus. At the same time, under the effect of piracetam the DA turnover was accelerated in the cortex and hypothalamus and delayed in the striatum, the noradrenaline turnover was accelerated in the brain stem, the 5-HT turnover was accelerated in the cortex and delayed in the striatum, stem and hypothalamus. Under the effect of aniracetam the DA level was reduced in the striatum and hypothalamus; the 5-HT level was also decreased in the hypothalamus and increased in the cortex and striatum. Aniracetam delayed the DA turnover in the striatum and the 5-HT turnover in the hypothalamus, accelerating the 5-HT turnover in the cortex, striatum and stem. The results obtained show that the changes induced in the cerebral biogenic monoamines participate in the mechanism of action of piracetam and aniracetam, whereby it seems that the analogies and differences in their effects on the cerebral biogenic monoamines play a definite role for the observed analogies and differences in the behavioural effects of these two "nootropic" compounds.

The involvement of heparan sulfate proteoglycans in stem cell differentiation and in malignant glioma

NASA Astrophysics Data System (ADS)

Kundu, Soumi; Xiong, Anqi; Forsberg-Nilsson, Karin

2016-04-01

Heparan sulfate (HS) proteoglycans (HSPG) are major components of the extracellular matrix. They interact with a plethora of macromolecules that are of physiological importance. The pattern of sulfation of the HS chain determines the specificity of these interactions. The enzymes that synthesize and degrade HS are thus key regulators of processes ranging from embryonic development to tissue homeostasis and tumor development. Formation of the nervous system is also critically dependent on appropriate HSPGs as shown by several studies on the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common primary malignant brain tumor among adults, and the prognosis is poor. Neural and glioma stem cells share several traits, including sustained proliferation and highly efficient migration in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside and the tumorigenic niche, including their interactions with components of the extracellular matrix (ECM). The levels of many of these components, for example HSPGs and enzymes involved in the biosynthesis and modification of HS are attenuated in gliomas. In this paper, HS regulation of pathways involved in neural differentiation and how these may be of importance for brain development are discussed. The literature suggesting that modifications of HS could regulate glioma growth and invasion is reviewed. Targeting the invasiveness of glioma cells by modulating HS may improve upon present therapeutic options, which only marginally enhance the survival of glioma patients.

Lineage analysis of quiescent regenerative stem cells in the adult brain by genetic labelling reveals spatially restricted neurogenic niches in the olfactory bulb.

PubMed

Giachino, Claudio; Taylor, Verdon

2009-07-01

The subventricular zone (SVZ) of the lateral ventricles is the major neurogenic region in the adult mammalian brain, harbouring neural stem cells within defined niches. The identity of these stem cells and the factors regulating their fate are poorly understood. We have genetically mapped a population of Nestin-expressing cells during postnatal development to study their potential and fate in vivo. Taking advantage of the recombination characteristics of a nestin::CreER(T2) allele, we followed a subpopulation of neural stem cells and traced their fate in a largely unrecombined neurogenic niche. Perinatal nestin::CreER(T2)-expressing cells give rise to multiple glial cell types and neurons, as well as to stem cells of the adult SVZ. In the adult SVZ nestin::CreER(T2)-expressing neural stem cells give rise to several neuronal subtypes in the olfactory bulb (OB). We addressed whether the same population of neural stem cells play a role in SVZ regeneration. Following anti-mitotic treatment to eliminate rapidly dividing progenitors, relatively quiescent nestin::CreER(T2)-targeted cells are spared and contribute to SVZ regeneration, generating new proliferating precursors and neuroblasts. Finally, we have identified neurogenic progenitors clustered in ependymal-like niches within the rostral migratory stream (RMS) of the OB. These OB-RMS progenitors generate neuroblasts that, upon transplantation, graft, migrate and differentiate into granule and glomerular neurons. In summary, using conditional lineage tracing we have identified neonatal cells that are the source of neurogenic and regenerative neural stem cells in the adult SVZ and occupy a novel neurogenic niche in the OB.

An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling.

PubMed

Hayakawa-Yano, Yoshika; Suyama, Satoshi; Nogami, Masahiro; Yugami, Masato; Koya, Ikuko; Furukawa, Takako; Zhou, Li; Abe, Manabu; Sakimura, Kenji; Takebayashi, Hirohide; Nakanishi, Atsushi; Okano, Hideyuki; Yano, Masato

2017-09-15

Cell type-specific transcriptomes are enabled by the action of multiple regulators, which are frequently expressed within restricted tissue regions. In the present study, we identify one such regulator, Quaking 5 (Qki5), as an RNA-binding protein (RNABP) that is expressed in early embryonic neural stem cells and subsequently down-regulated during neurogenesis. mRNA sequencing analysis in neural stem cell culture indicates that Qki proteins play supporting roles in the neural stem cell transcriptome and various forms of mRNA processing that may result from regionally restricted expression and subcellular localization. Also, our in utero electroporation gain-of-function study suggests that the nuclear-type Qki isoform Qki5 supports the neural stem cell state. We next performed in vivo transcriptome-wide protein-RNA interaction mapping to search for direct targets of Qki5 and elucidate how Qki5 regulates neural stem cell function. Combined with our transcriptome analysis, this mapping analysis yielded a bona fide map of Qki5-RNA interaction at single-nucleotide resolution, the identification of 892 Qki5 direct target genes, and an accurate Qki5-dependent alternative splicing rule in the developing brain. Last, our target gene list provides the first compelling evidence that Qki5 is associated with specific biological events; namely, cell-cell adhesion. This prediction was confirmed by histological analysis of mice in which Qki proteins were genetically ablated, which revealed disruption of the apical surface of the lateral wall in the developing brain. These data collectively indicate that Qki5 regulates communication between neural stem cells by mediating numerous RNA processing events and suggest new links between splicing regulation and neural stem cell states. © 2017 Hayakawa-Yano et al.; Published by Cold Spring Harbor Laboratory Press.

Yoga Therapy in Treating Patients With Malignant Brain Tumors

ClinicalTrials.gov

2017-07-27

Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

Electrophysiological measurement of human auditory function

NASA Technical Reports Server (NTRS)

Galambos, R.

1975-01-01

Contingent negative variations in the presence and amplitudes of brain potentials evoked by sound are considered. Evidence is produced that the evoked brain stem response to auditory stimuli is clearly related to brain events associated with cognitive processing of acoustic signals since their properties depend upon where the listener directs his attention, whether the signal is an expected event or a surprise, and when sound that is listened-for is heard at last.

Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model.

PubMed

Torrente, D; Avila, M F; Cabezas, R; Morales, L; Gonzalez, J; Samudio, I; Barreto, G E

2014-07-01

Traumatic brain injury (TBI) consists of a primary and a secondary insult characterized by a biochemical cascade that plays a crucial role in cell death in the brain. Despite the major improvements in the acute care of head injury victims, no effective strategies exist for preventing the secondary injury cascade. This lack of success might be due to that most treatments are aimed at targeting neuronal population, even if studies show that astrocytes play a key role after a brain damage. In this work, we propose a new model of in vitro traumatic brain-like injury and use paracrine factors released by human mesenchymal stem cells (hMSCs) as a neuroprotective strategy. Our results demonstrate that hMSC-conditioned medium increased wound closure and proliferation at 12 h and reduced superoxide production to control conditions. This was accompanied by changes in cell morphology and polarity index, as both parameters reflect the ability of cells to migrate toward the wound. These findings indicate that hMSC is an important regulator of oxidative stress production, enhances cells migration, and shall be considered as a useful neuroprotective approach for brain recovery following injury. © The Author(s) 2014.

Neurosurgery of the future: Deep brain stimulations and manipulations.

PubMed

Nicolaidis, Stylianos

2017-04-01

Important advances are afoot in the field of neurosurgery-particularly in the realms of deep brain stimulation (DBS), deep brain manipulation (DBM), and the newly introduced refinement "closed-loop" deep brain stimulation (CLDBS). Use of closed-loop technology will make both DBS and DBM more precise as procedures and will broaden their indications. CLDBS utilizes as feedback a variety of sources of electrophysiological and neurochemical afferent information about the function of the brain structures to be treated or studied. The efferent actions will be either electric, i.e. the classic excitatory or inhibitory ones, or micro-injection of such things as neural proteins and transmitters, neural grafts, implants of pluripotent stem cells or mesenchymal stem cells, and some variants of gene therapy. The pathologies to be treated, beside Parkinson's disease and movement disorders, include repair of neural tissues, neurodegenerative pathologies, psychiatric and behavioral dysfunctions, i.e. schizophrenia in its various guises, bipolar disorders, obesity, anorexia, drug addiction, and alcoholism. The possibility of using these new modalities to treat a number of cognitive dysfunctions is also under consideration. Because the DBS-CLDBS technology brings about a cross-fertilization between scientific investigation and surgical practice, it will also contribute to an enhanced understanding of brain function. Copyright © 2017. Published by Elsevier Inc.

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

PubMed Central

Torossian, Frédéric; Guerton, Bernadette; Anginot, Adrienne; Alexander, Kylie A.; Desterke, Christophe; Soave, Sabrina; Tseng, Hsu-Wen; Arouche, Nassim; Boutin, Laetitia; Kulina, Irina; Salga, Marjorie; Jose, Beulah; Pettit, Allison R.; Clay, Denis; Vlachos, Erica; Genet, Guillaume; Debaud, Charlotte; Denormandie, Philippe; Genet, François; Sims, Natalie A.; Banzet, Sébastien; Levesque, Jean-Pierre; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

2017-01-01

Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury–induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support. We demonstrate that oncostatin M (OSM) produced by activated macrophages promotes osteoblastic differentiation and mineralization of human muscle-derived stromal cells surrounding NHOs. The key role of OSM was confirmed using an experimental model of NHO in mice defective for the OSM receptor (OSMR). Our results provide strong evidence that macrophages contribute to NHO formation through the osteogenic action of OSM on muscle cells within an inflammatory context and suggest that OSM/OSMR could be a suitable therapeutic target. Altogether, the evidence of HSCs in ectopic bones growing at the expense of soft tissue in spinal cord/brain-injured patients indicates that inflammation and muscle contribute to HSC regulation by the brain-bone-blood triad. PMID:29093266

3 CFR 8446 - Proclamation 8446 of October 30, 2009. National Alzheimer's Disease Awareness Month, 2009

Code of Federal Regulations, 2010 CFR

2010-01-01

..., we must leave no avenue unexplored. Embryonic stem cells may hold the key for us to better understand... Executive Order lifting the ban on Federal funding for embryonic stem cell research, with proper guidelines... are now able to start treatments earlier, slowing the loss of brain cells and the progression of...

Current status of treating neurodegenerative disease with induced pluripotent stem cells.

PubMed

Pen, A E; Jensen, U B

2017-01-01

Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PPARγ agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells

PubMed Central

Pestereva, E; Kanakasabai, S; Bright, J J

2012-01-01

Background: Brain tumour stem cells (BTSCs) are a small population of cancer cells that exhibit self-renewal, multi-drug resistance, and recurrence properties. We have shown earlier that peroxisome proliferator-activated receptor gamma (PPARγ) agonists inhibit the expansion of BTSCs in T98G and U87MG glioma. In this study, we analysed the influence of PPARγ agonists on the expression of stemness and differentiation genes in BTSCs. Methods: The BTSCs were isolated from T98G and DB29 glioma cells, and cultured in neurobasal medium with epidermal growth factor+basic fibroblast growth factor. Proliferation was measured by WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H-5-tetrazolio]-1,3-benzene disulphonate) and 3H thymidine uptake assays, and gene expression was analysed by quantitative reverse--transcription PCR and Taqman array. The expression of CD133, SRY box 2, and nanog homeobox (Nanog) was also evaluated by western blotting, immunostaining, and flow cytometry. Results: We found that PPARγ agonists, ciglitazone and 15-deoxy-Δ12,14-ProstaglandinJ2, inhibited cell viability and proliferation of T98G- and DB29-BTSCs. The PPARγ agonists reduced the expansion of CD133+ BTSCs and altered the expression of stemness and differentiation genes. They also inhibited Sox2 while enhancing Nanog expression in BTSCs. Conclusion: These findings highlight that PPARγ agonists inhibit BTSC proliferation in association with altered expression of Sox2, Nanog, and other stemness genes. Therefore, targeting stemness genes in BTSCs could be a novel strategy in the treatment of glioblastoma. PMID:22531638

Using induced pluripotent stem cells derived neurons to model brain diseases.

PubMed

McKinney, Cindy E

2017-07-01

The ability to use induced pluripotent stem cells (iPSC) to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders. Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology. iPSC derived neurons, or other neural cell types, provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting. Thus, utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future. Many brain diseases across the spectrum of neurodevelopment, neurodegenerative and neuropsychiatric are being approached by iPSC models. The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells. In this mini-review, the importance of iPSC cell models validated for pluripotency, germline competency and function assessments is discussed. Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.