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Sample records for adult brain stem

  1. Stem Cell-Mediated Regeneration of the Adult Brain

    PubMed Central

    Jessberger, Sebastian

    2016-01-01

    Acute or chronic injury of the adult mammalian brain is often associated with persistent functional deficits as its potential for regeneration and capacity to rebuild lost neural structures is limited. However, the discovery that neural stem cells (NSCs) persist throughout life in discrete regions of the brain, novel approaches to induce the formation of neuronal and glial cells, and recently developed strategies to generate tissue for exogenous cell replacement strategies opened novel perspectives how to regenerate the adult brain. Here, we will review recently developed approaches for brain repair and discuss future perspectives that may eventually allow for developing novel treatment strategies in acute and chronic brain injury. PMID:27781019

  2. 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.

  3. 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

  4. Neurodevelopment. Live imaging of adult neural stem cell behavior in the intact and injured zebrafish brain.

    PubMed

    Barbosa, Joana S; Sanchez-Gonzalez, Rosario; Di Giaimo, Rossella; Baumgart, Emily Violette; Theis, Fabian J; Götz, Magdalena; Ninkovic, Jovica

    2015-05-15

    Adult neural stem cells are the source for restoring injured brain tissue. We used repetitive imaging to follow single stem cells in the intact and injured adult zebrafish telencephalon in vivo and found that neurons are generated by both direct conversions of stem cells into postmitotic neurons and via intermediate progenitors amplifying the neuronal output. We observed an imbalance of direct conversion consuming the stem cells and asymmetric and symmetric self-renewing divisions, leading to depletion of stem cells over time. After brain injury, neuronal progenitors are recruited to the injury site. These progenitors are generated by symmetric divisions that deplete the pool of stem cells, a mode of neurogenesis absent in the intact telencephalon. Our analysis revealed changes in the behavior of stem cells underlying generation of additional neurons during regeneration.

  5. Transcriptional profiling of adult neural stem-like cells from the human brain.

    PubMed

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.

  6. Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches.

    PubMed

    Rueger, Maria Adele; Androutsellis-Theotokis, Andreas

    2013-01-01

    In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells.

  7. Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications.

    PubMed

    Abou-Antoun, Tamara J; Hale, James S; Lathia, Justin D; Dombrowski, Stephen M

    2017-04-03

    Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

  8. Transcription levels of sirtuin family in neural stem cells and brain tissues of adult mice.

    PubMed

    Wang, H F; Li, Q; Feng, R L; Wen, T Q

    2012-09-10

    Neural stem cells (NSCs) has been used as a well-known model to investigate apoptosis, differentiation, maintenance of stem cells status, and therapy of neurological disease. The C17.2 NSCs line was produced after v-myc transformation of neural progenitor from mouse cerebellar cortex. Sirtuin family plays important roles involved in neuronal differentiation, genomic stability, lifespan, cell survival. However, little is known about gene expression variation of sirtuin family in C17.2 NSCs, primary NSCs, and different brain tissues in adult mice. Here, we confirmed that the mRNA expression levels of sirt2, 3, 4, 5, and 7 in E14.5 NSCs were significantly higher than in C17.2 NSCs, whereas that sirt 6 displayed an opposing mode. Moreover, a higher mRNA level of sirtuin family was observed in the adult mouse brain compared to C17.2 NSCs. In addition, histone deacetylase (HDAC) inhibitors nicotinamide and Trichostatin A (TSA) were used to explore differential changes at the transcriptional level of sirtuins. Results indicated that the expression of sirt1, sirt5 and sirt6 was significant downregulated by nicotinamide treatment. Whereas, a significant downregulation in sirt1 and sirt3 and a significant upregulation in sirt2, sirt4, sirt6, and sirt7 were observed in the treatment of TSA. Thus our studies indicate different sirtuin mRNA expression profiles between C17.2 NSCs, E14.5 NSCs and brain tissues, suggesting the transcriptional regulation of sirtuin family could be mediated by different histone acetylation.

  9. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  10. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

    PubMed

    Steib, Kathrin; Schäffner, Iris; Jagasia, Ravi; Ebert, Birgit; Lie, D Chichung

    2014-05-07

    Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.

  11. 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.

  12. 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.

  13. Transcranial Magnetic Stimulation of Human Adult Stem Cells in the Mammalian Brain

    PubMed Central

    Kremer, Karlea L.; Smith, Ashleigh E.; Sandeman, Lauren; Inglis, Joshua M.; Ridding, Michael C.; Koblar, Simon A.

    2016-01-01

    Introduction: The burden of stroke on the community is growing, and therefore, so is the need for a therapy to overcome the disability following stroke. Cellular-based therapies are being actively investigated at a pre-clinical and clinical level. Studies have reported the beneficial effects of exogenous stem cell implantation, however, these benefits are also associated with limited survival of implanted stem cells. This exploratory study investigated the use of transcranial magnetic stimulation (TMS) as a complementary therapy to increase stem cell survival following implantation of human dental pulp stem cells (DPSC) in the rodent cortex. Methods: Sprague-Dawley rats were anesthetized and injected with 6 × 105 DPSC or control media via an intracranial injection, and then received real TMS (TMS0.2 Hz) or sham TMS (TMSsham) every 2nd day beginning on day 3 post DPSC injection for 2 weeks. Brain sections were analyzed for the survival, migration and differentiation characteristics of the implanted cells. Results: In animals treated with DPSC and TMS0.2 Hz there were significantly less implanted DPSC and those that survived remained in the original cerebral hemisphere compared to animals that received TMSsham. The surviving implanted DPSC in TMS0.2 Hz were also found to express the apoptotic marker Caspase-3. Conclusions: We suggest that TMS at this intensity may cause an increase in glutamate levels, which promotes an unfavorable environment for stem cell implantation, proliferation and differentiation. It should be noted that only one paradigm of TMS was tested as this was conducted as a exploratory study, and further TMS paradigms should be investigated in the future. PMID:27013982

  14. 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.

  15. Generalized Potential of Adult Neural Stem Cells

    NASA Astrophysics Data System (ADS)

    Clarke, Diana L.; Johansson, Clas B.; Wilbertz, Johannes; Veress, Biborka; Nilsson, Erik; Karlström, Helena; Lendahl, Urban; Frisén, Jonas

    2000-06-01

    The differentiation potential of stem cells in tissues of the adult has been thought to be limited to cell lineages present in the organ from which they were derived, but there is evidence that some stem cells may have a broader differentiation repertoire. We show here that neural stem cells from the adult mouse brain can contribute to the formation of chimeric chick and mouse embryos and give rise to cells of all germ layers. This demonstrates that an adult neural stem cell has a very broad developmental capacity and may potentially be used to generate a variety of cell types for transplantation in different diseases.

  16. Age-related changes in stem cell dynamics, neurogenesis, apoptosis, and gliosis in the adult brain: a novel teleost fish model of negligible senescence.

    PubMed

    Traniello, Ian M; Sîrbulescu, Ruxandra F; Ilieş, Iulian; Zupanc, Günther K H

    2014-05-01

    Adult neurogenesis, the generation of new neurons in the adult central nervous system, is a reported feature of all examined vertebrate species. However, a dramatic decline in the rates of cell proliferation and neuronal differentiation occurs in mammals, typically starting near the onset of sexual maturation. In the present study, we examined possible age-related changes associated with adult neurogenesis in the brain of brown ghost knifefish (Apteronotus leptorhynchus), a teleost fish distinguished by its enormous neurogenic potential. Contrary to the well-established alterations in the mammalian brain during aging, in the brain of this teleostean species we could not find evidence for any significant age-related decline in the absolute levels of stem/progenitor cell proliferation, neuronal and glial differentiation, or long-term survival of newly generated cells. Moreover, there was no indication that the amount of glial fibrillary acidic protein or the number of apoptotic cells in the brain was altered significantly over the course of adult life. We hypothesize that this first demonstration of negligible cellular senescence in the vertebrate brain is related to the continued growth of this species and to the lack of reproductive senescence during adulthood. The establishment of the adult brain of this species as a novel model of negligible senescence provides new opportunities for the advancement of our understanding of the biology of aging and the fundamental mechanisms that underlie senescence in the brain.

  17. Adult Stem Cells from the Hyaluronic Acid-Rich Node and Duct System Differentiate into Neuronal Cells and Repair Brain Injury

    PubMed Central

    Lee, Seung J.; Park, Sang H.; Kim, Yu I.; Hwang, Sunhee; Kwon, Patrick M.; Han, In S.

    2014-01-01

    The existence of a hyaluronic acid-rich node and duct system (HAR-NDS) within the lymphatic and blood vessels was demonstrated previously. The HAR-NDS was enriched with small (3.0–5.0 μm in diameter), adult stem cells with properties similar to those of the very small embryonic-like stem cells (VSELs). Sca-1+Lin−CD45− cells were enriched approximately 100-fold in the intravascular HAR-NDS compared with the bone marrow. We named these adult stem cells “node and duct stem cells (NDSCs).” NDSCs formed colonies on C2C12 feeder layers, were positive for fetal alkaline phosphatase, and could be subcultured on the feeder layers. NDSCs were Oct4+Nanog+SSEA-1+Sox2+, while VSELs were Oct4+Nanog+SSEA-1+Sox2−. NDSCs had higher sphere-forming efficiency and proliferative potential than VSELs, and they were found to differentiate into neuronal cells in vitro. Injection of NDSCs into mice partially repaired ischemic brain damage. Thus, we report the discovery of potential adult stem cells that may be involved in tissue regeneration. The intravascular HAR-NDS may serve as a route that delivers these stem cells to their target tissues. PMID:25027245

  18. Comparative analysis of the frequency and distribution of stem and progenitor cells in the adult mouse brain.

    PubMed

    Golmohammadi, Mohammad G; Blackmore, Daniel G; Large, Beatrice; Azari, Hassan; Esfandiary, Ebrahim; Paxinos, George; Franklin, Keith B J; Reynolds, Brent A; Rietze, Rodney L

    2008-04-01

    The neurosphere assay can detect and expand neural stem cells (NSCs) and progenitor cells, but it cannot discriminate between these two populations. Given two assays have purported to overcome this shortfall, we performed a comparative analysis of the distribution and frequency of NSCs and progenitor cells detected in 400 mum coronal segments along the ventricular neuraxis of the adult mouse brain using the neurosphere assay, the neural colony forming cell assay (N-CFCA), and label-retaining cell (LRC) approach. We observed a large variation in the number of progenitor/stem cells detected in serial sections along the neuraxis, with the number of neurosphere-forming cells detected in individual 400 mum sections varying from a minimum of eight to a maximum of 891 depending upon the rostral-caudal coordinate assayed. Moreover, the greatest variability occurred in the rostral portion of the lateral ventricles, thereby explaining the large variation in neurosphere frequency previously reported. Whereas the overall number of neurospheres (3730 +/- 276) or colonies (4275 +/- 124) we detected along the neuraxis did not differ significantly, LRC numbers were significantly reduced (1186 +/- 188, 7 month chase) in comparison to both total colonies and neurospheres. Moreover, approximately two orders of magnitude fewer NSC-derived colonies (50 +/- 10) were detected using the N-CFCA as compared to LRCs. Given only 5% of the LRCs are cycling (BrdU+/Ki-67+) or competent to divide (BrdU+/Mcm-2+), and proliferate upon transfer to culture, it is unclear whether this technique selectively detects endogenous NSCs. Overall, caution should be taken with the interpretation and employment of all these techniques.

  19. An electrophysiological study of the in vitro, perfused brain stem-cerebellum of adult guinea-pig.

    PubMed Central

    Llinás, R; Mühlethaler, M

    1988-01-01

    1. We describe here a technique which allows the long-term in vitro survival of the perfused isolated brain stem-cerebellum of adult guinea-pig. The viability of this preparation was assessed by comparing the electrophysiological properties of individual neurones and of neuronal pools to those obtained in vivo or in brain slices. The areas investigated included the cerebellar cortex, the inferior olive and the pontine nuclei. 2. Cerebellar field potential and intra- and extracellular single-cell recordings could be obtained for as long as 15 h after the preparation was initially isolated. The waveforms of field potentials recorded at various depths in the cerebellar cortex following surface folial stimulation were similar to those recorded in vivo. Extracellular recordings from single Purkinje cells following white matter stimulation demonstrated antidromic as well as mossy- and climbing fibre-mediated excitation. Stimulation of the cerebellar surface elicited orthodromic parallel fibre excitation of Purkinje cells and basket-stellate and Golgi cell inhibition. 3. Intrasomatic and intradendritic recordings from Purkinje cells reproduced all the phenomenology described earlier under in vivo conditions and in vitro slice preparations. In addition, spontaneous excitatory synaptic potentials generating simple spikes (mossy fibre-parallel fibre-mediated activity) and complex spikes (climbing fibre-mediated activity) were consistently observed. 4. Extracellular field potentials and extra- and intracellular recordings from inferior olive neurones were similar to those previously shown for the mammalian inferior olive. 5. Intracellular recordings were also obtained from pontine nuclei neurones, a major source of mossy fibre afferents to the cerebellum. Stimulation of the contralateral superior cerebellar peduncle produced antidromic invasion of these neurones whereas stimulation of the ipsilateral inferior cerebral peduncle resulted in their orthodromic activation. 6. The

  20. Neural repair in the adult brain

    PubMed Central

    Jessberger, Sebastian

    2016-01-01

    Acute or chronic injury to the adult brain often results in substantial loss of neural tissue and subsequent permanent functional impairment. Over the last two decades, a number of approaches have been developed to harness the regenerative potential of neural stem cells and the existing fate plasticity of neural cells in the nervous system to prevent tissue loss or to enhance structural and functional regeneration upon injury. Here, we review recent advances of stem cell-associated neural repair in the adult brain, discuss current challenges and limitations, and suggest potential directions to foster the translation of experimental stem cell therapies into the clinic. PMID:26918167

  1. Childhood Brain Stem Glioma Treatment

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain stem gliomas may cause ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  2. Neural stem cell transplantation in mouse brain.

    PubMed

    Lee, Jean-Pyo; McKercher, Scott; Muller, Franz-Josef; Snyder, Evan Y

    2008-01-01

    Neural stem cells (NSCs) are the most primordial, least committed cells of the nervous system, and transplantation of these multipotent cells holds the promise of regenerative therapy for many central nervous system (CNS) diseases. This unit describes methods for NSC transplantation into neonatal mouse pups, embryonic mouse brain, and adult mouse brain. A description of options for detection of labeled donor cells in engrafted mouse brain is provided along with an example protocol for detecting lacZ-expressing cells in situ. Also included is a protocol for preparing NSCs for transplantation.

  3. Human fetal brain-derived neural stem/progenitor cells grafted into the adult epileptic brain restrain seizures in rat models of temporal lobe epilepsy.

    PubMed

    Lee, Haejin; Yun, Seokhwan; Kim, Il-Sun; Lee, Il-Shin; Shin, Jeong Eun; Park, Soo Chul; Kim, Won-Joo; Park, Kook In

    2014-01-01

    Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (∼34%), APC-CC1+ oligodendrocytes (∼28%), and GFAP+ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal

  4. Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

    PubMed Central

    Lee, Haejin; Yun, Seokhwan; Kim, Il-Sun; Lee, Il-Shin; Shin, Jeong Eun; Park, Soo Chul; Kim, Won-Joo; Park, Kook In

    2014-01-01

    Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (∼34%), APC-CC1+ oligodendrocytes (∼28%), and GFAP+ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal

  5. Treatment of adult MPSI mouse brains with IDUA-expressing mesenchymal stem cells decreases GAG deposition and improves exploratory behavior

    PubMed Central

    2012-01-01

    Background Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity. Methods MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses. Results After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months. Conclusions These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice. PMID:22520214

  6. Your brain under the microscope: the promise of stem cells.

    PubMed

    Marchetto, Maria C; Gage, Fred H

    2014-01-01

    Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. Scientists are just now beginning to improve their understanding of a third kind: induced pluripotent stem cells. Our authors describe how they were discovered, what they are, and why a growing number of researchers and clinicians believe that they may be one of the keys in helping address various brain disorders.

  7. Nop2 is expressed during proliferation of neural stem cells and in adult mouse and human brain.

    PubMed

    Kosi, Nina; Alić, Ivan; Kolačević, Matea; Vrsaljko, Nina; Jovanov Milošević, Nataša; Sobol, Margarita; Philimonenko, Anatoly; Hozák, Pavel; Gajović, Srećko; Pochet, Roland; Mitrečić, Dinko

    2015-02-09

    The nucleolar protein 2 gene encodes a protein specific for the nucleolus. It is assumed that it plays a role in the synthesis of ribosomes and regulation of the cell cycle. Due to its link to cell proliferation, higher expression of Nop2 indicates a worse tumor prognosis. In this work we used Nop2(gt1gaj) gene trap mouse strain. While lethality of homozygous animals suggested a vital role of this gene, heterozygous animals allowed the detection of expression of Nop2 in various tissues, including mouse brain. Histochemistry, immunohistochemistry and immunoelectron microscopy techniques, applied to a mature mouse brain, human brain and on mouse neural stem cells revealed expression of Nop2 in differentiating cells, including astrocytes, as well as in mature neurons. Nop2 was detected in various regions of mouse and human brain, mostly in large pyramidal neurons. In the human, Nop2 was strongly expressed in supragranular and infragranular layers of the somatosensory cortex and in layer III of the cingulate cortex. Also, Nop2 was detected in CA1 and the subiculum of the hippocampus. Subcellular analyses revealed predominant location of Nop2 within the dense fibrillar component of the nucleolus. To test if Nop2 expression correlates to cell proliferation occurring during tissue regeneration, we induced strokes in mice by middle cerebral artery occlusion. Two weeks after stroke, the number of Nop2/nestin double positive cells in the region affected by ischemia and the periventricular zone substantially increased. Our findings suggest a newly discovered role of Nop2 in both mature neurons and in cells possibly involved in the regeneration of nervous tissue.

  8. Isolation and Culture of Adult Zebrafish Brain-derived Neurospheres

    PubMed Central

    Lopez-Ramirez, Miguel A.; Calvo, Charles-Félix; Ristori, Emma; Thomas, Jean-Léon; Nicoli, Stefania

    2016-01-01

    The zebrafish is a highly relevant model organism for understanding the cellular and molecular mechanisms involved in neurogenesis and brain regeneration in vertebrates. However, an in-depth analysis of the molecular mechanisms underlying zebrafish adult neurogenesis has been limited due to the lack of a reliable protocol for isolating and culturing neural adult stem/progenitor cells. Here we provide a reproducible method to examine adult neurogenesis using a neurosphere assay derived from zebrafish whole brain or from the telencephalon, tectum and cerebellum regions of the adult zebrafish brain. The protocol involves, first the microdissection of zebrafish adult brain, then single cell dissociation and isolation of self-renewing multipotent neural stem/progenitor cells. The entire procedure takes eight days. Additionally, we describe how to manipulate gene expression in zebrafish neurospheres, which will be particularly useful to test the role of specific signaling pathways during adult neural stem/progenitor cell proliferation and differentiation in zebrafish. PMID:26967835

  9. Adult stem cell therapy: dream or reality?

    PubMed

    Moraleda, Jose M; Blanquer, Miguel; Bleda, Patricia; Iniesta, Paqui; Ruiz, Francisco; Bonilla, Sonia; Cabanes, Carmen; Tabares, Lucía; Martinez, Salvador

    2006-12-01

    Adult stem cells may be an invaluable source of plastic cells for tissue regeneration. The bone marrow contains different subpopulations of adult stem cells easily accessible for transplantation. However the therapeutic value of adult stem cell is a question of debate in the scientific community. We have investigated the potential benefits of adult hematopoietic stem cell transplantation in animal models of demyelinating and motor neuron diseases. Our results suggest that transplantation of HSC have direct and indirect neuroregenerative and neuroprotective effects.

  10. [Stem cells of mammalian brain: biology of the stem cells in vivo and in vitro].

    PubMed

    Viktorov, I V

    2001-01-01

    Stem cells are totipotent cells of the blastocyst (embryonal stem cells) and multipotent germinative cells of ento-, ecto-, and mesoderm that give rise to all tissues during embryogenesis. The stem cells have high proliferation activity and an unlimited capacity for self-production by symmetrical mitosis. Asymmetrical mitosis of the stem cells generates daughter cells ("progenitor cells") with unlimited proliferation potential. During differentiation, the progenitor cells give rise to definitive somatic cells. The stem and progenitor cells are preserved in most tissues of adult organism and provide for the constant replacement of the cells after their physiological death and damage. At the end of last century, stem cells were found in the brain of the adult mouse and rat and later in the brain of other mammals including humans. The subependymal zone of the lateral ventricles is considered the site of stem cells localization; however, there are indications of stem cells origination from ependyma while the subependymal zone serves as a collector of the progenitor cells where these cells divide. The problem of the localization of stem cells in a mature brain has not yet been resolved and is actively discussed. The stem and progenitor cells, as well as neuro- and gliogenesis, are most explored in the hippocampus and olfactory bulb. The progenitor cells migrate to the olfactory bulb from the subependymal zone of the lateral ventricles via a rostral migratory stream formed by the astrocytes, and then they differentiate to neural and glial cells. In the hippocampus, the neurons are formed in the subgranular zone of dentate gyrus. The discovery of stem and progenitor cells in the mature brain and their subsequent investigation point to an ongoing neuro- and gliogenesis in all periventricular sections of the brain and spinal cord during the whole animal or human lifespan. These processes proved to be related to the functional condition of CNS, and the de novo formed neural

  11. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats.

    PubMed

    Hargus, Gunnar; Cooper, Oliver; Deleidi, Michela; Levy, Adam; Lee, Kristen; Marlow, Elizabeth; Yow, Alyssa; Soldner, Frank; Hockemeyer, Dirk; Hallett, Penelope J; Osborn, Teresia; Jaenisch, Rudolf; Isacson, Ole

    2010-09-07

    Recent advances in deriving induced pluripotent stem (iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cell-derived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine- and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cell-derived DA neurons in regard to potential therapeutic applications.

  12. Adult human brain cell culture for neuroscience research.

    PubMed

    Gibbons, Hannah M; Dragunow, Mike

    2010-06-01

    Studies of the brain have progressed enormously through the use of in vivo and in vitro non-human models. However, it is unlikely such studies alone will unravel the complexities of the human brain and so far no neuroprotective treatment developed in animals has worked in humans. In this review we discuss the use of adult human brain cell culture methods in brain research to unravel the biology of the normal and diseased human brain. The advantages of using adult human brain cells as tools to study human brain function from both historical and future perspectives are discussed. In particular, studies using dissociated cultures of adult human microglia, astrocytes, oligodendrocytes and neurons are described and the applications of these types of study are evaluated. Alternative sources of human brain cells such as adult neural stem cells, induced pluripotent stem cells and slice cultures of adult human brain tissue are also reviewed. These adult human brain cell culture methods could benefit basic research and more importantly, facilitate the translation of basic neuroscience research to the clinic for the treatment of brain disorders.

  13. Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain.

    PubMed

    Pineda, Jose R; Daynac, Mathieu; Chicheportiche, Alexandra; Cebrian-Silla, Arantxa; Sii Felice, Karine; Garcia-Verdugo, Jose Manuel; Boussin, François D; Mouthon, Marc-André

    2013-04-01

    Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging.

  14. 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.

  15. Adult neurogenesis and its role in neuropsychiatric disease, brain repair and normal brain function.

    PubMed

    Braun, S M G; Jessberger, S

    2014-02-01

    Neural stem/progenitor cells (NSPCs) in the mammalian brain retain the ability to generate new neurones throughout life in discrete brain regions, through a process called adult neurogenesis. Adult neurogenesis, a dramatic form of adult brain circuitry plasticity, has been implicated in physiological brain function and appears to be of pivotal importance for certain forms of learning and memory. In addition, failing or altered neurogenesis has been associated with a variety of brain diseases such as major depression, epilepsy and age-related cognitive decline. Here we review recent advances in our understanding of the basic biology underlying the neurogenic process in the adult brain, focusing on mechanisms that regulate quiescence, proliferation and differentiation of NSPCs. In addition, we discuss how neurogenesis influences normal brain function, and in particular its role in memory formation, as well as its contribution to neuropsychiatric diseases. Finally, we evaluate the potential of targeting endogenous NSPCs for brain repair.

  16. 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.

  17. 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.

  18. Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages

    PubMed Central

    Waider, Jonas; Ziegler, Janina

    2016-01-01

    Recently, Trista North and colleagues showed that neuronal synthesis of serotonin is an essential key process for embryonic hematopoietic stem (HPS) cell production in zebrafish. Using their experimental design, they were able to show that neuronal serotonin activates the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor activity which in turn induces HPS cell formation. In our perspective, we give a short overview on established experimental approaches for serotonergic neurotransmission in vivo and in vitro and their potential to address putative contributions of serotonergic neurotransmission to physiological processes beyond the central nervous systems (CNS). We briefly introduce common features of brain serotonin-depleted, tryptophan hydroxylase-2 knockout mice, which can be applied to investigate the contribution of brain-derived serotonin to developmental and adult physiological processes outside the CNS. These models allow to analyzing gender-specific, HPA axis-dependent processes in female and male knockout mice during developmental and adult stages. We also highlight the application of human and mouse stem cell-derived serotonergic neurons as an independent research model as well as complementary experimental approach to transgenic animal models. In case of human serotonergic neurotransmission, human in vitro-generated neurons present a very promising and highly valuable experimental approach to address characteristics of human neuronal serotonin signaling on a molecular and cellular level. The combination of transgenic animal models and newly established stem cell technologies will provide powerful research platforms, which will help to answer yet unsolved mysteries of serotonergic neurotransmission. PMID:28078274

  19. Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages.

    PubMed

    Waider, Jonas; Ziegler, Janina; Lau, Thorsten

    2016-01-01

    Recently, Trista North and colleagues showed that neuronal synthesis of serotonin is an essential key process for embryonic hematopoietic stem (HPS) cell production in zebrafish. Using their experimental design, they were able to show that neuronal serotonin activates the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor activity which in turn induces HPS cell formation. In our perspective, we give a short overview on established experimental approaches for serotonergic neurotransmission in vivo and in vitro and their potential to address putative contributions of serotonergic neurotransmission to physiological processes beyond the central nervous systems (CNS). We briefly introduce common features of brain serotonin-depleted, tryptophan hydroxylase-2 knockout mice, which can be applied to investigate the contribution of brain-derived serotonin to developmental and adult physiological processes outside the CNS. These models allow to analyzing gender-specific, HPA axis-dependent processes in female and male knockout mice during developmental and adult stages. We also highlight the application of human and mouse stem cell-derived serotonergic neurons as an independent research model as well as complementary experimental approach to transgenic animal models. In case of human serotonergic neurotransmission, human in vitro-generated neurons present a very promising and highly valuable experimental approach to address characteristics of human neuronal serotonin signaling on a molecular and cellular level. The combination of transgenic animal models and newly established stem cell technologies will provide powerful research platforms, which will help to answer yet unsolved mysteries of serotonergic neurotransmission.

  20. Potential of adult neural stem cells in stroke therapy.

    PubMed

    Andres, Robert H; Choi, Raymond; Steinberg, Gary K; Guzman, Raphael

    2008-11-01

    Despite state-of-the-art therapy, clinical outcome after stroke remains poor, with many patients left permanently disabled and dependent on care. Stem cell therapy has evolved as a promising new therapeutic avenue for the treatment of stroke in experimental studies, and recent clinical trials have proven its feasibility and safety in patients. Replacement of damaged cells and restoration of function can be accomplished by transplantation of different cell types, such as embryonic, fetal or adult stem cells, human fetal tissue and genetically engineered cell lines. Adult neural stem cells offer the advantage of avoiding the ethical problems associated with embryonic or fetal stem cells and can be harvested as autologous grafts from the individual patients. Furthermore, stimulation of endogenous adult stem cell-mediated repair mechanisms in the brain might offer new avenues for stroke therapy without the necessity of transplantation. However, important scientific issues need to be addressed to advance our understanding of the molecular mechanisms underlying the critical steps in cell-based repair to allow the introduction of these experimental techniques into clinical practice. This review describes up-to-date experimental concepts using adult neural stem cells for the treatment of stroke.

  1. Comparative aspects of adult neural stem cell activity in vertebrates.

    PubMed

    Grandel, Heiner; Brand, Michael

    2013-03-01

    At birth or after hatching from the egg, vertebrate brains still contain neural stem cells which reside in specialized niches. In some cases, these stem cells are deployed for further postnatal development of parts of the brain until the final structure is reached. In other cases, postnatal neurogenesis continues as constitutive neurogenesis into adulthood leading to a net increase of the number of neurons with age. Yet, in other cases, stem cells fuel neuronal turnover. An example is protracted development of the cerebellar granular layer in mammals and birds, where neurogenesis continues for a few weeks postnatally until the granular layer has reached its definitive size and stem cells are used up. Cerebellar growth also provides an example of continued neurogenesis during adulthood in teleosts. Again, it is the granular layer that grows as neurogenesis continues and no definite adult cerebellar size is reached. Neuronal turnover is most clearly seen in the telencephalon of male canaries, where projection neurons are replaced in nucleus high vocal centre each year before the start of a new mating season--circuitry reconstruction to achieve changes of the song repertoire in these birds? In this review, we describe these and other examples of adult neurogenesis in different vertebrate taxa. We also compare the structure of the stem cell niches to find common themes in their organization despite different functions adult neurogenesis serves in different species. Finally, we report on regeneration of the zebrafish telencephalon after injury to highlight similarities and differences of constitutive neurogenesis and neuronal regeneration.

  2. Adult Stem Cells and Diseases of Aging

    PubMed Central

    Boyette, Lisa B.; Tuan, Rocky S.

    2014-01-01

    Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan. PMID:24757526

  3. BRAIN STEM SYSTEMS AND BEHAVIOR.

    DTIC Science & Technology

    BEHAVIOR, BLOOD CIRCULATION), SLEEP, EMOTIONS, BRAIN , STIMULATION (PHYSIOLOGY), HYPOTENSION, BLOOD PRESSURE, RESISTANCE(BIOLOGY), HEART, MUSCLES, RELAXATION(PHYSIOLOGY), CATS, AUTONOMIC NERVOUS SYSTEM, BLOOD VESSELS, ITALY

  4. Brain stem glioma: two case studies.

    PubMed

    Rosenblum, Ruth K

    2005-01-01

    The paths taken by each family in coming to terms with the dismal prognosis associated with brain stem glioma can be quite different. The case studies of 2 school-age girls diagnosed with a brain stem glioma within weeks of each other are presented. The multi-disciplinary team response to each family was individualized at each stage of diagnosis, treatment, and end-of-life care, as expected. The ultimate chronologic union of these 2 families as each child neared death was somewhat uncanny. The experience of each family, and their relationship with the team through this process, was an intense challenge and learning experience.

  5. Left Brain/Right Brain Learning for Adult Education.

    ERIC Educational Resources Information Center

    Garvin, Barbara

    1986-01-01

    Contrasts and compares the theory and practice of adult education as it relates to the issue of right brain/left brain learning. The author stresses the need for a whole-brain approach to teaching and suggests that adult educators, given their philosophical directions, are the perfect potential users of this integrated system. (Editor/CT)

  6. Typical and atypical stem cells in the brain, vitamin C effect and neuropathology.

    PubMed

    Nualart, Francisco; Salazar, Katterine; Oyarce, Karina; Cisternas, Pedro; Jara, Nery; Silva-Álvarez, Carmen; Pastor, Patricia; Martínez, Fernando; García, Andrea; García-Robles, María de los Ángeles; Tapia, Juan Carlos

    2012-01-01

    Stem cells are considered a valuable cellular resource for tissue replacement therapies in most brain disorders. Stem cells have the ability to self-replicate and differentiate into numerous cell types, including neurons, oligodendrocytes and astrocytes. As a result, stem cells have been considered the "holy grail" of modern medical neuroscience. Despite their tremendous therapeutic potential, little is known about the mechanisms that regulate their differentiation. In this review, we analyze stem cells in embryonic and adult brains, and illustrate the differentiation pathways that give origin to most brain cells. We also evaluate the emergent role of the well known anti-oxidant, vitamin C, in stem cell differentiation. We believe that a complete understanding of all molecular players, including vitamin C, in stem cell differentiation will positively impact on the use of stem cell transplantation for neurodegenerative diseases.

  7. [Application prospect of adult stem cells in male infertility].

    PubMed

    Yang, Rui-Feng; Xiong, Cheng-Liang

    2013-05-01

    The study on stem cells is a hot field in biomedical science in recent years, and has furthered from laboratory to clinical application. Stem cells, according to their developmental stage and differential properties, can be divided into embryonic stem cells, induced PS cells and adult stem cells, among which, adult stem cells have already been applied to the clinical treatment of many systemic diseases. Currently, the study of spermatogonial stem cells and adult stem cells is in the front of the basic researches on the treatment of male infertility, but the time has not yet arrived for their clinical application. This paper outlines the application prospect of adult stem cells in male infertility.

  8. Adherent neural stem (NS) cells from fetal and adult forebrain.

    PubMed

    Pollard, Steven M; Conti, Luciano; Sun, Yirui; Goffredo, Donato; Smith, Austin

    2006-07-01

    Stable in vitro propagation of central nervous system (CNS) stem cells would offer expanded opportunities to dissect basic molecular, cellular, and developmental processes and to model neurodegenerative disease. CNS stem cells could also provide a source of material for drug discovery assays and cell replacement therapies. We have recently reported the generation of adherent, symmetrically expandable, neural stem (NS) cell lines derived both from mouse and human embryonic stem cells and from fetal forebrain (Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A. 2005. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3(9):e283). These NS cells retain neuronal and glial differentiation potential after prolonged passaging and are transplantable. NS cells are likely to comprise the resident stem cell population within heterogeneous neurosphere cultures. Here we demonstrate that similar NS cell cultures can be established from the adult mouse brain. We also characterize the growth factor requirements for NS cell derivation and self-renewal. We discuss our current understanding of the relationship of NS cell lines to physiological progenitor cells of fetal and adult CNS.

  9. Brain and Spinal Cord Tumors in Adults

    MedlinePlus

    ... Search Search En Español Category Cancer A-Z Brain and Spinal Cord Tumors in Adults If you have a brain or spinal cord tumor or are close to ... cope. Here you can find out all about brain and spinal cord tumors in adults, including risk ...

  10. Computed tomography of the brain stem with intrathecal metrizamide. Part 1: the normal brain stem

    SciTech Connect

    Mawad, M.E.; Silver, A.J.; Hilal, S.K.; Ganti, S.R.

    1983-03-01

    Detailed anatomy of the brain stem and cervicomedullary junction can be accurately demonstrated with metrizamide computed tomographic cisternography. Specifically surface anatomy is unusually well outlined. Nine distinct and easily recognizable levels of section are described: four levels in the medulla, three in the pons, and two in the mesencephalon. Surface features of the brain stem, fine details in the floor of the fourth ventricle, cranial nerves, and vascular structures are shown and discussed.

  11. The longest telomeres: a general signature of adult stem cell compartments

    PubMed Central

    Flores, Ignacio; Canela, Andres; Vera, Elsa; Tejera, Agueda; Cotsarelis, George; Blasco, María A.

    2008-01-01

    Identification of adult stem cells and their location (niches) is of great relevance for regenerative medicine. However, stem cell niches are still poorly defined in most adult tissues. Here, we show that the longest telomeres are a general feature of adult stem cell compartments. Using confocal telomere quantitative fluorescence in situ hybridization (telomapping), we find gradients of telomere length within tissues, with the longest telomeres mapping to the known stem cell compartments. In mouse hair follicles, we show that cells with the longest telomeres map to the known stem cell compartments, colocalize with stem cell markers, and behave as stem cells upon treatment with mitogenic stimuli. Using K15-EGFP reporter mice, which mark hair follicle stem cells, we show that GFP-positive cells have the longest telomeres. The stem cell compartments in small intestine, testis, cornea, and brain of the mouse are also enriched in cells with the longest telomeres. This constitutes the description of a novel general property of adult stem cell compartments. Finally, we make the novel finding that telomeres shorten with age in different mouse stem cell compartments, which parallels a decline in stem cell functionality, suggesting that telomere loss may contribute to stem cell dysfunction with age. PMID:18283121

  12. CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells.

    PubMed

    Pfenninger, Cosima V; Roschupkina, Teona; Hertwig, Falk; Kottwitz, Denise; Englund, Elisabet; Bengzon, Johan; Jacobsen, Sten Eirik; Nuber, Ulrike A

    2007-06-15

    Human brain tumor stem cells have been enriched using antibodies against the surface protein CD133. An antibody recognizing CD133 also served to isolate normal neural stem cells from fetal human brain, suggesting a possible lineage relationship between normal neural and brain tumor stem cells. Whether CD133-positive brain tumor stem cells can be derived from CD133-positive neural stem or progenitor cells still requires direct experimental evidence, and an important step toward such investigations is the identification and characterization of normal CD133-presenting cells in neurogenic regions of the embryonic and adult brain. Here, we present evidence that CD133 is a marker for embryonic neural stem cells, an intermediate radial glial/ependymal cell type in the early postnatal stage, and for ependymal cells in the adult brain, but not for neurogenic astrocytes in the adult subventricular zone. Our findings suggest two principal possibilities for the origin of brain tumor stem cells: a derivation from CD133-expressing cells, which are normally not present in the adult brain (embryonic neural stem cells and an early postnatal intermediate radial glial/ependymal cell type), or from CD133-positive ependymal cells in the adult brain, which are, however, generally regarded as postmitotic. Alternatively, brain tumor stem cells could be derived from proliferative but CD133-negative neurogenic astrocytes in the adult brain. In the latter case, brain tumor development would involve the production of CD133.

  13. Primary brain tumours in adults.

    PubMed

    Ricard, Damien; Idbaih, Ahmed; Ducray, François; Lahutte, Marion; Hoang-Xuan, Khê; Delattre, Jean-Yves

    2012-05-26

    Important advances have been made in the understanding and management of adult gliomas and primary CNS lymphomas--the two most common primary brain tumours. Progress in imaging has led to a better analysis of the nature and grade of these tumours. Findings from large phase 3 studies have yielded some standard treatments for gliomas, and have confirmed the prognostic value of specific molecular alterations. High-throughput methods that enable genome-wide analysis of tumours have improved the knowledge of tumour biology, which should lead to a better classification of gliomas and pave the way for so-called targeted therapy trials. Primary CNS lymphomas are a group of rare non-Hodgkin lymphomas. High-dose methotrexate-based regimens increase survival, but the standards of care and the place of whole-brain radiotherapy remain unclear, and are likely to depend on the age of the patient. The focus now is on the development of new polychemotherapy regimens to reduce or defer whole-brain radiotherapy and its delayed complications.

  14. Translational research of adult stem cell therapy.

    PubMed

    Suzuki, Gen

    2015-11-26

    Congestive heart failure (CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.

  15. Catalog of gene expression in adult neural stem cells and their in vivo microenvironment

    SciTech Connect

    Williams, Cecilia; Wirta, Valtteri; Meletis, Konstantinos; Wikstroem, Lilian; Carlsson, Leif; Frisen, Jonas; Lundeberg, Joakim . E-mail: joakim.lundeberg@biotech.kth.se

    2006-06-10

    Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.

  16. Widespread sites of brain stem ventilatory chemoreceptors.

    PubMed

    Coates, E L; Li, A; Nattie, E E

    1993-07-01

    We produced local tissue acidosis in various brain stem regions with 1-nl injections of acetazolamide (AZ) to locate the sites of central chemoreception. To determine whether the local acidosis resulted in a stimulation of breathing, we performed the experiment in chloralose-urethan anesthetized vagotomized carotid-denervated (cats) paralyzed servo-ventilated cats and rats and measured phrenic nerve activity (PNA) as the response index. Measurements of extracellular brain tissue pH by glass microelectrodes showed that AZ injections induced a change in pH at the injection center equivalent to that produced by an increase in end-tidal PCO2 of approximately 36 Torr and that the change in brain pH was limited to a tissue volume with a radius of < 350 microns. We found AZ injections sites that caused a significant increase in PNA to be located 1) within 800 microns of the ventrolateral medullary surface at locations within traditional rostral and caudal chemosensitive areas and the intermediate area, 2) within the vicinity of the nucleus tractus solitarii, and 3) within the vicinity of the locus coeruleus. Single AZ injections produced increases in PNA that were < or = 69% of the maximum value observed with an increase in end-tidal PCO2. We conclude that central chemoreceptors are distributed at many locations within the brain stem, all within 1.5 mm of the surface, and that stimulation of a small fraction of all central chemoreceptors can result in a large ventilatory response.

  17. Generation of pluripotent stem cells from adult human testis.

    PubMed

    Conrad, Sabine; Renninger, Markus; Hennenlotter, Jörg; Wiesner, Tina; Just, Lothar; Bonin, Michael; Aicher, Wilhelm; Bühring, Hans-Jörg; Mattheus, Ulrich; Mack, Andreas; Wagner, Hans-Joachim; Minger, Stephen; Matzkies, Matthias; Reppel, Michael; Hescheler, Jürgen; Sievert, Karl-Dietrich; Stenzl, Arnulf; Skutella, Thomas

    2008-11-20

    Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis. Cellular and molecular characterization of these cells revealed many similarities to human embryonic stem cells, and the germline stem cells produced teratomas after transplantation into immunodeficient mice. The human adult germline stem cells differentiated into various types of somatic cells of all three germ layers when grown under conditions used to induce the differentiation of human embryonic stem cells. We conclude that the generation of human adult germline stem cells from testicular biopsies may provide simple and non-controversial access to individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells.

  18. Adult Stem Cell Therapy for Stroke: Challenges and Progress

    PubMed Central

    Bang, Oh Young; Kim, Eun Hee; Cha, Jae Min; Moon, Gyeong Joon

    2016-01-01

    Stroke is one of the leading causes of death and physical disability among adults. It has been 15 years since clinical trials of stem cell therapy in patients with stroke have been conducted using adult stem cells like mesenchymal stem cells and bone marrow mononuclear cells. Results of randomized controlled trials showed that adult stem cell therapy was safe but its efficacy was modest, underscoring the need for new stem cell therapy strategies. The primary limitations of current stem cell therapies include (a) the limited source of engraftable stem cells, (b) the presence of optimal time window for stem cell therapies, (c) inherited limitation of stem cells in terms of growth, trophic support, and differentiation potential, and (d) possible transplanted cell-mediated adverse effects, such as tumor formation. Here, we discuss recent advances that overcome these hurdles in adult stem cell therapy for stroke. PMID:27733032

  19. Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens

    SciTech Connect

    Louis, D.N.; Rubio, M.P.; Correa, K.M.; Gusella, J.F.; Deimling, A. von )

    1993-09-01

    Brain stem gliomas are pediatric astrocytomas that histologically resemble adult supratentorial astrocytomas such as gliobastomas multiforme (GBM). The molecular genetic studies have suggested that adult GBM can be divided into two genetic subsets: Tumors with p53 tumor suppressor gene mutations and chromosome 17p loss that occur more commonly in younger patients; and tumors with epidermal growth factor receptor (EGFR) gene amplification that occur more commonly in older patients. Brain stem gliomas have not been studied since biopsies of these tumors are rare and extremely small. The authors investigated the molecular genetic composition of seven brain stem glioblastomas (two small biopsies, five autopsies) using polymerase chain reaction (PCR) assays for chromosomal loss, gene mutation and gene amplification. Four cases lost portions of chromosome 17p that included the 53p gene. These four cases and one additional case had mutations in the p53 gene. None of the cases showed amplification of the EGFR gene. Allelic losses of the long arm of chromosome 10 were noted in four cases. These results suggest similarities between pediatric brain stem glioblastomas and those GBM that occur in younger adult patients, and confirm the utility of PCR-based means of studying small and archival brain tumor specimens. 47 refs., 7 figs., 2 tabs.

  20. Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

    PubMed Central

    Bond, Allison M.; Ming, Guo-li; Song, Hongjun

    2015-01-01

    Summary Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID:26431181

  1. 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.

  2. Immune Influence on Adult Neural Stem Cell Regulation and Function

    PubMed Central

    Carpentier, Pamela A.; Palmer, Theo D.

    2009-01-01

    Neural stem cells (NSCs) lie at the heart of central nervous system development and repair, and deficiency or dysregulation of NSCs or their progeny can have significant consequences at any stage of life. Immune signaling is emerging as one of the influential variables that define resident NSC behavior. Perturbations in local immune signaling accompany virtually every injury or disease state and signaling cascades that mediate immune activation, resolution, or chronic persistence influence resident stem and progenitor cells. Some aspects of immune signaling are beneficial, promoting intrinsic plasticity and cell replacement, while others appear to inhibit the very type of regenerative response that might restore or replace neural networks lost in injury or disease. Here we review known and speculative roles that immune signaling plays in the postnatal and adult brain, focusing on how environments encountered in disease or injury may influence the activity and fate of endogenous or transplanted NSCs. PMID:19840551

  3. NFL-lipid nanocapsules for brain neural stem cell targeting in vitro and in vivo.

    PubMed

    Carradori, Dario; Saulnier, Patrick; Préat, Véronique; des Rieux, Anne; Eyer, Joel

    2016-09-28

    The replacement of injured neurons by the selective stimulation of neural stem cells in situ represents a potential therapeutic strategy for the treatment of neurodegenerative diseases. The peptide NFL-TBS.40-63 showed specific interactions towards neural stem cells of the subventricular zone. The aim of our work was to produce a NFL-based drug delivery system able to target neural stem cells through the selective affinity between the peptide and these cells. NFL-TBS.40-63 (NFL) was adsorbed on lipid nanocapsules (LNC) whom targeting efficiency was evaluated on neural stem cells from the subventricular zone (brain) and from the central canal (spinal cord). NFL-LNC were incubated with primary neural stem cells in vitro or injected in vivo in adult rat brain (right lateral ventricle) or spinal cord (T10). NFL-LNC interactions with neural stem cells were different depending on the origin of the cells. NFL-LNC showed a preferential uptake by neural stem cells from the brain, while they did not interact with neural stem cells from the spinal cord. The results obtained in vivo correlate with the results observed in vitro, demonstrating that NFL-LNC represent a promising therapeutic strategy to selectively deliver bioactive molecules to brain neural stem cells.

  4. Adult stem cell-based apexogenesis

    PubMed Central

    Li, Yao; Shu, Li-Hong; Yan, Ming; Dai, Wen-Yong; Li, Jun-Jun; Zhang, Guang-Dong; Yu, Jin-Hua

    2014-01-01

    Generally, the dental pulp needs to be removed when it is infected, and root canal therapy (RCT) is usually required in which infected dental pulp is replaced with inorganic materials (paste and gutta percha). This treatment approach ultimately brings about a dead tooth. However, pulp vitality is extremely important to the tooth itself, since it provides nutrition and acts as a biosensor to detect the potential pathogenic stimuli. Despite the reported clinical success rate, RCT-treated teeth are destined to be devitalized, brittle and susceptible to postoperative fracture. Recently, the advances and achievements in the field of stem cell biology and regenerative medicine have inspired novel biological approaches to apexogenesis in young patients suffering from pulpitis or periapical periodontitis. This review mainly focuses on the benchtop and clinical regeneration of root apex mediated by adult stem cells. Moreover, current strategies for infected pulp therapy are also discussed here. PMID:25332909

  5. 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

  6. Axonal control of the adult neural stem cell niche.

    PubMed

    Tong, Cheuk Ka; Chen, Jiadong; Cebrián-Silla, Arantxa; Mirzadeh, Zaman; Obernier, Kirsten; Guinto, Cristina D; Tecott, Laurence H; García-Verdugo, Jose Manuel; Kriegstein, Arnold; Alvarez-Buylla, Arturo

    2014-04-03

    The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSCs) in the walls of the lateral ventricles of the adult brain. How the adult brain's neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C.

  7. Live Imaging of Adult Neural Stem Cells in Rodents

    PubMed Central

    Ortega, Felipe; Costa, Marcos R.

    2016-01-01

    The generation of cells of the neural lineage within the brain is not restricted to early development. New neurons, oligodendrocytes, and astrocytes are produced in the adult brain throughout the entire murine life. However, despite the extensive research performed in the field of adult neurogenesis during the past years, fundamental questions regarding the cell biology of adult neural stem cells (aNSCs) remain to be uncovered. For instance, it is crucial to elucidate whether a single aNSC is capable of differentiating into all three different macroglial cell types in vivo or these distinct progenies constitute entirely separate lineages. Similarly, the cell cycle length, the time and mode of division (symmetric vs. asymmetric) that these cells undergo within their lineage progression are interesting questions under current investigation. In this sense, live imaging constitutes a valuable ally in the search of reliable answers to the previous questions. In spite of the current limitations of technology new approaches are being developed and outstanding amount of knowledge is being piled up providing interesting insights in the behavior of aNSCs. Here, we will review the state of the art of live imaging as well as the alternative models that currently offer new answers to critical questions. PMID:27013941

  8. Adult stem cells in neural repair: Current options, limitations and perspectives.

    PubMed

    Mariano, Eric Domingos; Teixeira, Manoel Jacobsen; Marie, Suely Kazue Nagahashi; Lepski, Guilherme

    2015-03-26

    Stem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseases that defy doctors and researchers around the world. Stem cells can be divided into three main groups: (1) embryonic stem cells; (2) fetal stem cells; and (3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration.

  9. Retentive multipotency of adult dorsal root ganglia stem cells.

    PubMed

    Singh, Rabindra P; Cheng, Ying-Hua; Nelson, Paul; Zhou, Feng C

    2009-01-01

    Preservation of neural stem cells (NSCs) in the adult peripheral nervous system (PNS) has recently been confirmed. However, it is not clear whether peripheral NSCs possess predestined, bona fide phenotypes or a response to innate developmental cues. In this study, we first demonstrated the longevity, multipotency, and high fidelity of sensory features of postmigrating adult dorsal root ganglia (aDRG) stem cells. Derived from aDRG and after 4-5 years in culture without dissociating, the aDRG NSCs were found capable of proliferation, expressing neuroepithelial, neuronal, and glial markers. Remarkably, these aDRG NSCs expressed sensory neuronal markers vesicular glutamate transporter 2 (VGluT2--glutamate terminals), transient receptor potential vanilloid 1 (TrpV1--capsaicin sensitive), phosphorylated 200 kDa neurofilaments (pNF200--capsaicin insensitive, myelinated), and the serotonin transporter (5-HTT), which normally is transiently expressed in developing DRG. Furthermore, in response to neurotrophins, the aDRG NSCs enhanced TrpV1 expression upon exposure to nerve growth factor (NGF), but not to brain-derived neurotrophic factor (BDNF). On the contrary, BDNF increased the expression of NeuN. Third, the characterization of aDRG NSCs was demonstrated by transplantation of red fluorescent-expressing aDRG NSCs into injured spinal cord. These cells expressed nestin, Hu, and beta-III-tubulin (immature neuronal markers), GFAP (astrocyte marker) as well as sensory neural marker TrpV1 (capsaicin sensitive) and pNF200 (mature, capsaicin insensitive, myelinated). Our results demonstrated that the postmigrating neural crest adult DRG stem cells not only preserved their multipotency but also were retentive in sensory potency despite the age and long-term ex vivo status.

  10. 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

  11. Posterior foss avenous angiomas with drainage through the brain stem

    SciTech Connect

    Damiano, T.R.; Truwit, C.L. ); Dowd, C.F. ); Symonds, D.L. )

    1994-04-01

    To describe 11 cases of posterior fossa venous angiomas with drainage through the brain stem. Eleven cases of posterior fossa venous angioma with drainage through the brain stem were evaluated using MR. Correlation with known routes of venous drainage for the cerebellum and brain stem is made. Six of the 11 venous angiomas were found in the cerebellum, four in the brain stem; one involved both the cerebellum and brain stem. The cerebellar venous angiomas drained to subependymal veins about the fourth ventricle and dorsal pons. These then connected with an enlarged transmesencephalic or transpontine vein, to drain anteriorly to the anterior pontine veins. The brain stem angiomas had variable drainage depending on location. Evidence of hemorrhage was seen in five cases. Cerebellar and brain stem venous angiomas have several potential routes of drainage, including an enlarged vein traversing the pons, midbrain, or medulla. A knowledge of the normal venous anatomy of this region helps to understand the occurrence of these uncommon routes of venous drainage. 15 refs., 8 figs., 1 tab.

  12. Epigenetic choreographers of neurogenesis in the adult mammalian brain

    PubMed Central

    Ma, Dengke K; Marchetto, Maria Carolina; Guo, Junjie U; Ming, Guo-li; Gage, Fred H; Song, Hongjun

    2012-01-01

    Epigenetic mechanisms regulate cell differentiation during embryonic development and also serve as important interfaces between genes and the environment in adulthood. Neurogenesis in adults, which generates functional neural cell types from adult neural stem cells, is dynamically regulated by both intrinsic state-specific cell differentiation cues and extrinsic neural niche signals. Epigenetic regulation by DNA and histone modifiers, non-coding RNAs and other self-sustained mechanisms can lead to relatively long-lasting biological effects and maintain functional neurogenesis throughout life in discrete regions of the mammalian brain. Here, we review recent evidence that epigenetic mechanisms carry out diverse roles in regulating specific aspects of adult neurogenesis and highlight the implications of such epigenetic regulation for neural plasticity and disorders. PMID:20975758

  13. Yoga Therapy in Treating Patients With Malignant Brain Tumors

    ClinicalTrials.gov

    2017-01-17

    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

  14. 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.

  15. Adult stem cells: hopes and hypes of regenerative medicine.

    PubMed

    Dulak, Józef; Szade, Krzysztof; Szade, Agata; Nowak, Witold; Józkowicz, Alicja

    2015-01-01

    Stem cells are self-renewing cells that can differentiate into specialized cell type(s). Pluripotent stem cells, i.e. embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC) differentiate into cells of all three embryonic lineages. Multipotent stem cells, like hematopoietic stem cells (HSC), can develop into multiple specialized cells in a specific tissue. Unipotent cells differentiate only into one cell type, like e.g. satellite cells of skeletal muscle. There are many examples of successful clinical applications of stem cells. Over million patients worldwide have benefited from bone marrow transplantations performed for treatment of leukemias, anemias or immunodeficiencies. Skin stem cells are used to heal severe burns, while limbal stem cells can regenerate the damaged cornea. Pluripotent stem cells, especially the patient-specific iPSC, have a tremendous therapeutic potential, but their clinical application will require overcoming numerous drawbacks. Therefore, the use of adult stem cells, which are multipotent or unipotent, can be at present a more achievable strategy. Noteworthy, some studies ascribed particular adult stem cells as pluripotent. However, despite efforts, the postulated pluripotency of such events like "spore-like cells", "very small embryonic-like stem cells" or "multipotent adult progenitor cells" have not been confirmed in stringent independent studies. Also plasticity of the bone marrow-derived cells which were suggested to differentiate e.g. into cardiomyocytes, has not been positively verified, and their therapeutic effect, if observed, results rather from the paracrine activity. Here we discuss the examples of recent studies on adult stem cells in the light of current understanding of stem cell biology.

  16. Syrinx of the Spinal Cord and Brain Stem

    MedlinePlus

    ... the Spinal Cord and Brain Stem Symptoms Diagnosis Treatment Medical Dictionary Also of Interest (Quiz) Horner Syndrome (Video) Overview of the Nervous System (News) Youth With Type 2 Diabetes Often Face Complications (News) Study Tracks Bleeding Risk ...

  17. Axonal Control of the Adult Neural Stem Cell Niche

    PubMed Central

    Tong, Cheuk Ka; Chen, Jiadong; Cebrián-Silla, Arantxa; Mirzadeh, Zaman; Obernier, Kirsten; Guinto, Cristina D.; Tecott, Laurence H.; García-Verdugo, Jose Manuel; Kriegstein, Arnold; Alvarez-Buylla, Arturo

    2014-01-01

    SUMMARY The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSC) in the walls of the lateral ventricles of the adult brain. How the adult brain’s neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C. PMID:24561083

  18. 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.

  19. Investigation of genes important in neurodevelopment disorders in adult human brain.

    PubMed

    Maussion, Gilles; Diallo, Alpha B; Gigek, Carolina O; Chen, Elizabeth S; Crapper, Liam; Théroux, Jean-Francois; Chen, Gary G; Vasuta, Cristina; Ernst, Carl

    2015-10-01

    Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs. Analysis of DNA interaction sites in neural stem cells reveals high (40-50 %) overlap between proliferating and differentiating cells for each gene in temporal space. Studies in adult brain demonstrate that consensus sites are similar to NSCs but occur at different genomic locations. We also performed expression analyses using BrainSpan data for NDD-associated genes SATB2, EHMT1, FMR1, MECP2, MBD5, CTNND2, RAI1, CHD8, GRIN2A, GRIN2B, TCF4, SCN2A, and DYRK1A and find high expression of these genes in adult brain, at least comparable to developing human brain, confirming that genes associated with NDDs likely have a role in adult tissue. Adult function of genes associated with NDDs might be important in clinical disease presentation and may be suitable targets for therapeutic intervention.

  20. Training stem cells for treatment of malignant brain tumors.

    PubMed

    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

    2014-09-26

    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.

  1. Acupuncture stimulation induces neurogenesis in adult brain.

    PubMed

    Nam, Min-Ho; Ahn, Kwang Seok; Choi, Seung-Hoon

    2013-01-01

    The discovery of adult neurogenesis was a turning point in the field of neuroscience. Adult neurogenesis offers an enormous possibility to open a new therapeutic paradigm of neurodegenerative diseases and stroke. Recently, several studies suggested that acupuncture may enhance adult neurogenesis. Acupuncture has long been an important treatment for brain diseases in the East Asia. The scientific mechanisms of acupuncture treatment for the diseases, such as Alzheimer's disease, Parkinson's disease, and stroke, have not been clarified yet; however, the neurogenic effect of acupuncture can be a possible reason. Here, we have reviewed the studies on the effect of stimulation at various acupoints for neurogenesis, such as ST36 and GV20. The suggested mechanisms are also discussed including upregulation of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, basic fibroblast growth factor and neuropeptide Y, and activation of the function of primo vascular system.

  2. Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain.

    PubMed

    Feliciano, David M; Bordey, Angélique; Bonfanti, Luca

    2015-09-18

    Two decades after the discovery that neural stem cells (NSCs) populate some regions of the mammalian central nervous system (CNS), deep knowledge has been accumulated on their capacity to generate new neurons in the adult brain. This constitutive adult neurogenesis occurs throughout life primarily within remnants of the embryonic germinal layers known as "neurogenic sites." Nevertheless, some processes of neurogliogenesis also occur in the CNS parenchyma commonly considered as "nonneurogenic." This "noncanonical" cell genesis has been the object of many claims, some of which turned out to be not true. Indeed, it is often an "incomplete" process as to its final outcome, heterogeneous by several measures, including regional location, progenitor identity, and fate of the progeny. These aspects also strictly depend on the animal species, suggesting that persistent neurogenic processes have uniquely adapted to the brain anatomy of different mammals. Whereas some examples of noncanonical neurogenesis are strictly parenchymal, others also show stem cell niche-like features and a strong link with the ventricular cavities. This work will review results obtained in a research field that expanded from classic neurogenesis studies involving a variety of areas of the CNS outside of the subventricular zone (SVZ) and subgranular zone (SGZ). It will be highlighted how knowledge concerning noncanonical neurogenic areas is still incomplete owing to its regional and species-specific heterogeneity, and to objective difficulties still hampering its full identification and characterization.

  3. ADULT NEURAL STEM CELLS: RESPONSE TO STROKE INJURY AND POTENTIAL FOR THERAPEUTIC APPLICATIONS

    PubMed Central

    Barkho, Basam Z.; Zhao, Xinyu

    2011-01-01

    The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries. PMID:21466483

  4. 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.

  5. Brain Stem Hypoplasia Associated with Cri-du-Chat Syndrome

    PubMed Central

    Hong, Jin Ho; 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. PMID:24265573

  6. Gadobutrol Versus Gadopentetate Dimeglumine or Gadobenate Dimeglumine Before DCE-MRI in Diagnosing Patients With Multiple Sclerosis, Grade II-IV Glioma, or Brain Metastases

    ClinicalTrials.gov

    2017-03-22

    Adult Anaplastic (Malignant) Meningioma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Neoplasm; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Primary Melanocytic Lesion of Meninges; Adult Supratentorial Primitive Neuroectodermal Tumor; Malignant Adult Intracranial Hemangiopericytoma; Metastatic Malignant Neoplasm in the Brain; Multiple Sclerosis; Recurrent Adult Brain Neoplasm

  7. Large-scale live imaging of adult neural stem cells in their endogenous niche.

    PubMed

    Dray, Nicolas; Bedu, Sébastien; Vuillemin, Nelly; Alunni, Alessandro; Coolen, Marion; Krecsmarik, Monika; Supatto, Willy; Beaurepaire, Emmanuel; Bally-Cuif, Laure

    2015-10-15

    Live imaging of adult neural stem cells (aNSCs) in vivo is a technical challenge in the vertebrate brain. Here, we achieve long-term imaging of the adult zebrafish telencephalic neurogenic niche and track a population of >1000 aNSCs over weeks, by taking advantage of fish transparency at near-infrared wavelengths and of intrinsic multiphoton landmarks. This methodology enables us to describe the frequency, distribution and modes of aNSCs divisions across the entire germinal zone of the adult pallium, and to highlight regional differences in these parameters.

  8. Brain self-protection: the role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia.

    PubMed

    Li, Bin; Piao, Chun-Shu; Liu, Xiao-Yun; Guo, Wen-Ping; Xue, Yue-Qiang; Duan, Wei-Ming; Gonzalez-Toledo, Maria E; Zhao, Li-Ru

    2010-04-23

    Convincing evidence has shown that brain ischemia causes the proliferation of neural stem cells/neural progenitor cells (NSCs/NPCs) in both the subventricular zone (SVZ) and the subgranular zone (SGZ) of adult brain. The role of brain ischemia-induced NSC/NPC proliferation, however, has remained unclear. Here we have determined whether brain ischemia-induced amplification of the NSCs/NPCs in adult brain is required for brain self-protection. The approach of intracerebroventricular (ICV) infusion of cytosine arabinoside (Ara-C), an inhibitor for cell proliferation, for the first 7days after brain ischemia was used to block ischemia-induced NSC/NPC proliferation. We observed that ICV infusion of Ara-C caused a complete blockade of NSC/NPC proliferation in the SVZ and a dramatic reduction of NSC/NPC proliferation in the SGZ. Additionally, as a result of the inhibition of ischemia-induced NSC/NPC pool amplification, the number of neurons in the hippocampal CA1 and CA3 was significantly reduced, the infarction size was significantly enlarged, and neurological deficits were significantly worsened after focal brain ischemia. We also found that an NSC/NPC-conditioned medium showed neuroprotective effects in vitro and that adult NSC/NPC-released brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are required for NSC/NPC-conditioned medium-induced neuroprotection. These data suggest that NSC/NPC-generated trophic factors are neuroprotective and that brain ischemia-triggered NSC/NPC proliferation is crucial for brain protection. This study provides insights into the contribution of endogenous NSCs/NPCs to brain self-protection in adult brain after ischemia injury.

  9. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration.

    PubMed

    Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan

    2016-06-21

    Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.

  10. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration

    PubMed Central

    Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan

    2016-01-01

    Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications. PMID:27338364

  11. Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation

    PubMed Central

    Encinas, Juan M.; Vazquez, Marcelo E.; Switzer, Robert C.; Chamberland, Dennis W.; Nick, Harry; Levine, Howard G.; Scarpa, Philip J.; Enikolopov, Grigori; Steindler, Dennis A.

    2012-01-01

    Generation of new neurons in the adult brain, a process that is likely to be essential for learning, memory, and mood regulation, is impaired by radiation. Therefore, radiation exposure might have not only such previously expected consequences as increased probability of developing cancer, but might also impair cognitive function and emotional stability. Radiation exposure is encountered in settings ranging from cancer therapy to space travel; evaluating the neurogenic risks of radiation requires identifying the at-risk populations of stem and progenitor cells in the adult brain. Here we have used a novel reporter mouse line to find that early neural progenitors are selectively affected by conditions simulating the space radiation environment. This is reflected both in a decrease in the number of these progenitors in the neurogenic regions and in an increase in the number of dying cells in these regions. Unexpectedly, we found that quiescent neural stem cells, rather than their rapidly dividing progeny, are most sensitive to radiation. Since these stem cells are responsible for adult neurogenesis, their death would have a profound impact on the production of new neurons in the irradiated adult brain. Our finding raises an important concern about cognitive and emotional risks associated with radiation exposure. PMID:18076878

  12. Great promise of tissue-resident adult stem/progenitor cells in transplantation and cancer therapies.

    PubMed

    Mimeault, Murielle; Batra, Surinder K

    2012-01-01

    Recent progress in tissue-resident adult stem/progenitor cell research has inspired great interest because these immature cells from your own body can act as potential, easily accessible cell sources for cell transplantation in regenerative medicine and cancer therapies. The use of adult stem/progenitor cells endowed with a high self-renewal ability and multilineage differentiation potential, which are able to regenerate all the mature cells in the tissues from their origin, offers great promise in replacing non-functioning or lost cells and regenerating diseased and damaged tissues. The presence of a small subpopulation of adult stem/progenitor cells in most tissues and organs provides the possibility of stimulating their in vivo differentiation, or of using their ex vivo expanded progenies for cell-replacement and gene therapies with multiple applications in humans without a high-risk of graft rejection and major side effects. Among the diseases that could be treated by adult stem cell-based therapies are hematopoietic and immune disorders, multiple degenerative disorders such as Parkinson's and Alzheimer's diseases, Types 1 and 2 diabetes mellitus as well as skin, eye, liver, lung, tooth and cardiovascular disorders. In addition, a combination of the current cancer treatments with an adjuvant treatment consisting of an autologous or allogeneic adult stem/progenitor cell transplantation also represents a promising strategy for treating and even curing diverse aggressive, metastatic, recurrent and lethal cancers. In this chapter, we reviewed the most recent advancements on the characterization of phenotypic and functional properties of adult stem/progenitor cell types found in bone marrow, heart, brain and other tissues and discussed their therapeutic implications in the stem cell-based transplantation therapy.

  13. 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.

  14. Prion diseases and adult neurogenesis: How do prions counteract the brain's endogenous repair machinery?

    PubMed Central

    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. PMID:24831876

  15. GABA regulates synaptic integration of newly generated neurons in the adult brain

    NASA Astrophysics Data System (ADS)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  16. Cellular immortality in brain tumours: an integration of the cancer stem cell paradigm.

    PubMed

    Rahman, Ruman; Heath, Rachel; Grundy, Richard

    2009-04-01

    Brain tumours are a diverse group of neoplasms that continue to present a formidable challenge in our attempt to achieve curable intervention. Our conceptual framework of human brain cancer has been redrawn in the current decade. There is a gathering acceptance that brain tumour formation is a phenotypic outcome of dysregulated neurogenesis, with tumours viewed as abnormally differentiated neural tissue. In relation, there is accumulating evidence that brain tumours, similar to leukaemia and many solid tumours, are organized as a developmental hierarchy which is maintained by a small fraction of cells endowed with many shared properties of tissue stem cells. Proof that neurogenesis persists throughout adult life, compliments this concept. Although the cancer cell of origin is unclear, the proliferative zones that harbour stem cells in the embryonic, post-natal and adult brain are attractive candidates within which tumour-initiation may ensue. Dysregulated, unlimited proliferation and an ability to bypass senescence are acquired capabilities of cancerous cells. These abilities in part require the establishment of a telomere maintenance mechanism for counteracting the shortening of chromosomal termini. A strategy based upon the synthesis of telomeric repeat sequences by the ribonucleoprotein telomerase, is prevalent in approximately 90% of human tumours studied, including the majority of brain tumours. This review will provide a developmental perspective with respect to normal (neurogenesis) and aberrant (tumourigenesis) cellular turnover, differentiation and function. Within this context our current knowledge of brain tumour telomere/telomerase biology will be discussed with respect to both its developmental and therapeutic relevance to the hierarchical model of brain tumourigenesis presented by the cancer stem cell paradigm.

  17. REST regulation of gene networks in adult neural stem cells

    PubMed Central

    Mukherjee, Shradha; Brulet, Rebecca; Zhang, Ling; Hsieh, Jenny

    2016-01-01

    Adult hippocampal neural stem cells generate newborn neurons throughout life due to their ability to self-renew and exist as quiescent neural progenitors (QNPs) before differentiating into transit-amplifying progenitors (TAPs) and newborn neurons. The mechanisms that control adult neural stem cell self-renewal are still largely unknown. Conditional knockout of REST (repressor element 1-silencing transcription factor) results in precocious activation of QNPs and reduced neurogenesis over time. To gain insight into the molecular mechanisms by which REST regulates adult neural stem cells, we perform chromatin immunoprecipitation sequencing and RNA-sequencing to identify direct REST target genes. We find REST regulates both QNPs and TAPs, and importantly, ribosome biogenesis, cell cycle and neuronal genes in the process. Furthermore, overexpression of individual REST target ribosome biogenesis or cell cycle genes is sufficient to induce activation of QNPs. Our data define novel REST targets to maintain the quiescent neural stem cell state. PMID:27819263

  18. REST regulation of gene networks in adult neural stem cells.

    PubMed

    Mukherjee, Shradha; Brulet, Rebecca; Zhang, Ling; Hsieh, Jenny

    2016-11-07

    Adult hippocampal neural stem cells generate newborn neurons throughout life due to their ability to self-renew and exist as quiescent neural progenitors (QNPs) before differentiating into transit-amplifying progenitors (TAPs) and newborn neurons. The mechanisms that control adult neural stem cell self-renewal are still largely unknown. Conditional knockout of REST (repressor element 1-silencing transcription factor) results in precocious activation of QNPs and reduced neurogenesis over time. To gain insight into the molecular mechanisms by which REST regulates adult neural stem cells, we perform chromatin immunoprecipitation sequencing and RNA-sequencing to identify direct REST target genes. We find REST regulates both QNPs and TAPs, and importantly, ribosome biogenesis, cell cycle and neuronal genes in the process. Furthermore, overexpression of individual REST target ribosome biogenesis or cell cycle genes is sufficient to induce activation of QNPs. Our data define novel REST targets to maintain the quiescent neural stem cell state.

  19. Reversible neurotoxicity following hyperfractionated radiation therapy of brain stem glioma

    SciTech Connect

    Griebel, M.; Friedman, H.S.; Halperin, E.C.; Wiener, M.D.; Marks, L.; Oakes, W.J.; Hoffman, J.M.; DeLong, G.R.; Schold, S.C.; Hockenberger, B. )

    1991-01-01

    Two patients with brain stem gliomas were treated with hyperfractionated radiation therapy (HFR) (7,020 and 7,560 cGy, respectively). Despite initial clinical improvement during irradiation, both patients demonstrated clinical deterioration approximately 3 weeks after completion of radiotherapy. Cranial magnetic resonance imaging (MRI) revealed a progressive increase in distribution of abnormal brain stem signal consistent with either tumor or edema. {sup 18}FDG positron emission tomography (PET) was obtained in one patient and demonstrated a hypermetabolic lesion at diagnosis and a hypometabolic lesion at the time of clinical deterioration postirradiation. Management with a tapering dose of dexamethasone alone resulted in marked clinical (both patients) and radiographic (one patient) improvement, allowing reduction or discontinuation of this medication. These results suggest that patients with brain stem tumors demonstrating clinical and radiographic evidence of progressive tumor shortly after completion of HFR should be initially managed conservatively with dexamethasone, since these findings may be manifestations of reversible radiation-related neurotoxicity.

  20. The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells

    SciTech Connect

    Khalifa, Shaden A.M.; Medina, Philippe de; Erlandsson, Anna; El-Seedi, Hesham R.; Silvente-Poirot, Sandrine; Poirot, Marc

    2014-04-11

    Highlights: • Dendrogenin A and B are new aminoalkyl oxysterols. • Dendrogenins stimulated neural stem cells proliferation. • Dendrogenins induce neuronal outgrowth from neurospheres. • Dendrogenins provide new therapeutic options for neurodegenerative disorders. - Abstract: Dendrogenin A (DDA) and dendrogenin B (DDB) are new aminoalkyl oxysterols which display re-differentiation of tumor cells of neuronal origin at nanomolar concentrations. We analyzed the influence of dendrogenins on adult mice neural stem cell proliferation, sphere formation and differentiation. DDA and DDB were found to have potent proliferative effects in neural stem cells. Additionally, they induce neuronal outgrowth from neurospheres during in vitro cultivation. Taken together, our results demonstrate a novel role for dendrogenins A and B in neural stem cell proliferation and differentiation which further increases their likely importance to compensate for neuronal cell loss in the brain.

  1. 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.

  2. Human brain stem structures respond differentially to noxious heat.

    PubMed

    Ritter, Alexander; Franz, Marcel; Dietrich, Caroline; Miltner, Wolfgang H R; Weiss, Thomas

    2013-01-01

    Concerning the physiological correlates of pain, the brain stem is considered to be one core region that is activated by noxious input. In animal studies, different slopes of skin heating (SSH) with noxious heat led to activation in different columns of the midbrain periaqueductal gray (PAG). The present study aimed at finding a method for differentiating structures in PAG and other brain stem structures, which are associated with different qualities of pain in humans according to the structures that were associated with different behavioral significances to noxious thermal stimulation in animals. Brain activity was studied by functional MRI in healthy subjects in response to steep and shallow SSH with noxious heat. We found differential activation to different SSH in the PAG and the rostral ventromedial medulla (RVM). In a second experiment, we demonstrate that the different SSH were associated with different pain qualities. Our experiments provide evidence that brainstem structures, i.e., the PAG and the RVM, become differentially activated by different SSH. Therefore, different SSH can be utilized when brain stem structures are investigated and when it is aimed to activate these structures differentially. Moreover, percepts of first pain were elicited by shallow SSH whereas percepts of second pain were elicited by steep SSH. The stronger activation of these brain stem structures to SSH, eliciting percepts of second vs. first pain, might be of relevance for activating different coping strategies in response to the noxious input with the two types of SSH.

  3. The stem cell secretome and its role in brain repair.

    PubMed

    Drago, Denise; Cossetti, Chiara; Iraci, Nunzio; Gaude, Edoardo; Musco, Giovanna; Bachi, Angela; Pluchino, Stefano

    2013-12-01

    Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors. This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues. Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair. This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS.

  4. The stem cell secretome and its role in brain repair

    PubMed Central

    Drago, Denise; Cossetti, Chiara; Iraci, Nunzio; Gaude, Edoardo; Musco, Giovanna; Bachi, Angela; Pluchino, Stefano

    2014-01-01

    Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors. This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues. Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair. This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS. PMID:23827856

  5. Not(ch) just development: Notch signalling in the adult brain

    PubMed Central

    Ables, Jessica L.; Breunig, Joshua J.; Eisch, Amelia J.; Rakic, Pasko

    2011-01-01

    The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway. PMID:21505516

  6. Intestinal stem cells in the adult Drosophila midgut

    SciTech Connect

    Jiang, Huaqi; Edgar, Bruce A.

    2011-11-15

    Drosophila has long been an excellent model organism for studying stem cell biology. Notably, studies of Drosophila's germline stem cells have been instrumental in developing the stem cell niche concept. The recent discovery of somatic stem cells in adult Drosophila, particularly the intestinal stem cells (ISCs) of the midgut, has established Drosophila as an exciting model to study stem cell-mediated adult tissue homeostasis and regeneration. Here, we review the major signaling pathways that regulate the self-renewal, proliferation and differentiation of Drosophila ISCs, discussing how this regulation maintains midgut homeostasis and mediates regeneration of the intestinal epithelium after injury. -- Highlights: Black-Right-Pointing-Pointer The homeostasis and regeneration of adult fly midguts are mediated by ISCs. Black-Right-Pointing-Pointer Damaged enterocytes induce the proliferation of intestinal stem cells (ISC). Black-Right-Pointing-Pointer EGFR and Jak/Stat signalings mediate compensatory ISC proliferation. Black-Right-Pointing-Pointer Notch signaling regulates ISC self-renewal and differentiation.

  7. Adult neural stem cells: Long-term self-renewal, replenishment by the immune system, or both?

    PubMed

    Beltz, Barbara S; Cockey, Emily L; Li, Jingjing; Platto, Jody F; Ramos, Kristina A; Benton, Jeanne L

    2015-05-01

    The current model of adult neurogenesis in mammals suggests that adult-born neurons are generated by stem cells that undergo long-term self-renewal, and that a lifetime supply of stem cells resides in the brain. In contrast, it has recently been demonstrated that adult-born neurons in crayfish are generated by precursors originating in the immune system. This is particularly interesting because studies done many years ago suggest that a similar mechanism might exist in rodents and humans, with bone marrow providing stem cells that can generate neurons. However, the relevance of these findings for natural mechanisms underlying adult neurogenesis in mammals is not clear, because of uncertainties at many levels. We argue here that the recent findings in crayfish send a strong signal to re-examine existing data from rodents and humans, and to design new experiments that will directly test the contributions of the immune system to adult neurogenesis in mammals.

  8. Traumatic Brain Injury Activation of the Adult Subventricular Zone Neurogenic Niche

    PubMed Central

    Chang, Eun Hyuk; Adorjan, Istvan; Mundim, Mayara V.; Sun, Bin; Dizon, Maria L. V.; Szele, Francis G.

    2016-01-01

    Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI. PMID:27531972

  9. Development and specification of cerebellar stem and progenitor cells in zebrafish: from embryo to adult

    PubMed Central

    2013-01-01

    Background Teleost fish display widespread post-embryonic neurogenesis originating from many different proliferative niches that are distributed along the brain axis. During the development of the central nervous system (CNS) different cell types are produced in a strict temporal order from increasingly committed progenitors. However, it is not known whether diverse neural stem and progenitor cell types with restricted potential or stem cells with broad potential are maintained in the teleost fish brain. Results To study the diversity and output of neural stem and progenitor cell populations in the zebrafish brain the cerebellum was used as a model brain region, because of its well-known architecture and development. Transgenic zebrafish lines, in vivo imaging and molecular markers were used to follow and quantify how the proliferative activity and output of cerebellar progenitor populations progress. This analysis revealed that the proliferative activity and progenitor marker expression declines in juvenile zebrafish before they reach sexual maturity. Furthermore, this correlated with the diminished repertoire of cell types produced in the adult. The stem and progenitor cells derived from the upper rhombic lip were maintained into adulthood and they actively produced granule cells. Ventricular zone derived progenitor cells were largely quiescent in the adult cerebellum and produced a very limited number of glia and inhibitory inter-neurons. No Purkinje or Eurydendroid cells were produced in fish older than 3 months. This suggests that cerebellar cell types are produced in a strict temporal order from distinct pools of increasingly committed stem and progenitor cells. Conclusions Our results in the zebrafish cerebellum show that neural stem and progenitor cell types are specified and they produce distinct cell lineages and sub-types of brain cells. We propose that only specific subtypes of brain cells are continuously produced throughout life in the teleost fish

  10. 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

  11. Traumatic Brain Injury Severity Affects Neurogenesis in Adult Mouse Hippocampus.

    PubMed

    Wang, Xiaoting; Gao, Xiang; Michalski, Stephanie; Zhao, Shu; Chen, Jinhui

    2016-04-15

    Traumatic brain injury (TBI) has been proven to enhance neural stem cell (NSC) proliferation in the hippocampal dentate gyrus. However, various groups have reported contradictory results on whether TBI increases neurogenesis, partially due to a wide range in the severities of injuries seen with different TBI models. To address whether the severity of TBI affects neurogenesis in the injured brain, we assessed neurogenesis in mouse brains receiving different severities of controlled cortical impact (CCI) with the same injury device. The mice were subjected to mild, moderate, or severe TBI by a CCI device. The effects of TBI severity on neurogenesis were evaluated at three stages: NSC proliferation, immature neurons, and newly-generated mature neurons. The results showed that mild TBI did not affect neurogenesis at any of the three stages. Moderate TBI promoted NSC proliferation without increasing neurogenesis. Severe TBI increased neurogenesis at all three stages. Our data suggest that the severity of injury affects adult neurogenesis in the hippocampus, and thus it may partially explain the inconsistent results of different groups regarding neurogenesis following TBI. Further understanding the mechanism of TBI-induced neurogenesis may provide a potential approach for using endogenous NSCs to protect against neuronal loss after trauma.

  12. A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking

    PubMed Central

    Ratajczak, M Z

    2015-01-01

    This review presents a novel view and working hypothesis about the hierarchy within the adult bone marrow stem cell compartment and the still-intriguing question of whether adult bone marrow contains primitive stem cells from early embryonic development, such as cells derived from the epiblast, migrating primordial germ cells or yolk sac-derived hemangioblasts. It also presents a novel view of the mechanisms that govern stem cell mobilization and homing, with special emphasis on the role of the complement cascade as a trigger for egress of hematopoietic stem cells from bone marrow into blood as well as the emerging role of novel homing factors and priming mechanisms that support stromal-derived factor 1-mediated homing of hematopoietic stem/progenitor cells after transplantation. PMID:25486871

  13. Guidelines for Better Communication with Brain Impaired Adults

    MedlinePlus

    ... are here Home Guidelines for Better Communication with Brain Impaired Adults Printer-friendly version Communicating with a loved one with a brain disorder can indeed be challenging. Finding the right ...

  14. 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

  15. Muscle Stem Cells: A Model System for Adult Stem Cell Biology.

    PubMed

    Cornelison, Ddw; Perdiguero, Eusebio

    2017-01-01

    Skeletal muscle stem cells, originally termed satellite cells for their position adjacent to differentiated muscle fibers, are absolutely required for the process of skeletal muscle repair and regeneration. In the last decade, satellite cells have become one of the most studied adult stem cell systems and have emerged as a standard model not only in the field of stem cell-driven tissue regeneration but also in stem cell dysfunction and aging. Here, we provide background in the field and discuss recent advances in our understanding of muscle stem cell function and dysfunction, particularly in the case of aging, and the potential involvement of muscle stem cells in genetic diseases such as the muscular dystrophies.

  16. Adult stem cells underlying lung regeneration.

    PubMed

    Xian, Wa; McKeon, Frank

    2012-03-01

    Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.

  17. Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) CT in Children and Young Adults With Brain Tumors

    ClinicalTrials.gov

    2016-09-07

    Acoustic Schwannoma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Supratentorial Ependymoma; Meningeal Melanocytoma; Newly Diagnosed Childhood Ependymoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood

  18. Growth hormone (GH), brain development and neural stem cells.

    PubMed

    Waters, M J; Blackmore, D G

    2011-12-01

    A range of observations support a role for GH in development and function of the brain. These include altered brain structure in GH receptor null mice, and impaired cognition in GH deficient rodents and in a subgroup of GH receptor defective patients (Laron dwarfs). GH has been shown to alter neurogenesis, myelin synthesis and dendritic branching, and both the GH receptor and GH itself are expressed widely in the brain. We have found a population of neural stem cells which are activated by GH infusion, and which give rise to neurons in mice. These stem cells are activated by voluntary exercise in a GH-dependent manner. Given the findings that local synthesis of GH occurs in the hippocampus in response to a memory task, and that GH replacement improves memory and cognition in rodents and humans, these new observations warrant a reappraisal of the clinical importance of GH replacement in GH deficient states.

  19. Stem cell sources for clinical islet transplantation in type 1 diabetes: embryonic and adult stem cells.

    PubMed

    Miszta-Lane, Helena; Mirbolooki, Mohammadreza; James Shapiro, A M; Lakey, Jonathan R T

    2006-01-01

    Lifelong immunosuppressive therapy and inadequate sources of transplantable islets have led the islet transplantation benefits to less than 0.5% of type 1 diabetics. Whereas the potential risk of infection by animal endogenous viruses limits the uses of islet xeno-transplantation, deriving islets from stem cells seems to be able to overcome the current problems of islet shortages and immune compatibility. Both embryonic (derived from the inner cell mass of blastocysts) and adult stem cells (derived from adult tissues) have shown controversial results in secreting insulin in vitro and normalizing hyperglycemia in vivo. ESCs research is thought to have much greater developmental potential than adult stem cells; however it is still in the basic research phase. Existing ESC lines are not believed to be identical or ideal for generating islets or beta-cells and additional ESC lines have to be established. Research with ESCs derived from humans is controversial because it requires the destruction of a human embryo and/or therapeutic cloning, which some believe is a slippery slope to reproductive cloning. On the other hand, adult stem cells are already in some degree specialized, recipients may receive their own stem cells. They are flexible but they have shown mixed degree of availability. Adult stem cells are not pluripotent. They may not exist for all organs. They are difficult to purify and they cannot be maintained well outside the body. In order to draw the future avenues in this field, existent discrepancies between the results need to be clarified. In this study, we will review the different aspects and challenges of using embryonic or adult stem cells in clinical islet transplantation for the treatment of type 1 diabetes.

  20. Adult stem cells and their ability to differentiate.

    PubMed

    Tarnowski, Maciej; Sieron, Aleksander L

    2006-08-01

    This is a review of the current status of knowledge on adult stem cells as well as the criteria and evidence for their potential to transform into different cell types and cell lineages. Reports on stem cell sources, focusing on tissues from adult subjects, were also investigated. Numerous reports have been published on the search for early markers of both stem cells and the precursors of various cell lineages. The question is still open about the characteristics of the primary stem cell. The existing proofs and hypotheses have not yielded final solutions to this problem. From a practical point of view it is also crucial to find a minimal set of markers determining the phenotypes of the precursor cells of a particular cell lineage. Several lines of evidence seem to bring closer the day when we will be able to detect the right stem cell niche and successfully isolate precursor cells that are needed for the treatment of a particular disorder. Recent reports on cases of cancer in patients subjected to stem cell therapy are yet another controversial issue looked into in this review, although the pros and cons emerging from the results of published studies still do not provide satisfying evidence to fully understand this issue.

  1. Cranial irradiation induces bone marrow-derived microglia in adult mouse brain tissue.

    PubMed

    Okonogi, Noriyuki; Nakamura, Kazuhiro; Suzuki, Yoshiyuki; Suto, Nana; Suzue, Kazutomo; Kaminuma, Takuya; Nakano, Takashi; Hirai, Hirokazu

    2014-07-01

    Postnatal hematopoietic progenitor cells do not contribute to microglial homeostasis in adult mice under normal conditions. However, previous studies using whole-body irradiation and bone marrow (BM) transplantation models have shown that adult BM cells migrate into the brain tissue and differentiate into microglia (BM-derived microglia; BMDM). Here, we investigated whether cranial irradiation alone was sufficient to induce the generation of BMDM in the adult mouse brain. Transgenic mice that express green fluorescent protein (GFP) under the control of a murine stem cell virus (MSCV) promoter (MSCV-GFP mice) were used. MSCV-GFP mice express GFP in BM cells but not in the resident microglia in the brain. Therefore, these mice allowed us to detect BM-derived cells in the brain without BM reconstitution. MSCV-GFP mice, aged 8-12 weeks, received 13.0 Gy irradiation only to the cranium, and BM-derived cells in the brain were quantified at 3 and 8 weeks after irradiation. No BM-derived cells were detected in control non-irradiated MSCV-GFP mouse brains, but numerous GFP-labeled BM-derived cells were present in the brain stem, basal ganglia and cerebral cortex of the irradiated MSCV-GFP mice. These BM-derived cells were positive for Iba1, a marker for microglia, indicating that GFP-positive BM-derived cells were microglial in nature. The population of BMDM was significantly greater at 8 weeks post-irradiation than at 3 weeks post-irradiation in all brain regions examined. Our results clearly show that cranial irradiation alone is sufficient to induce the generation of BMDM in the adult mouse.

  2. Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury

    PubMed Central

    Hasan, Anwarul; Deeb, George; Rahal, Rahaf; Atwi, Khairallah; Mondello, Stefania; Marei, Hany Elsayed; Gali, Amr; Sleiman, Eliana

    2017-01-01

    Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge potential for application in the treatment of TBI. MSCs have immunosuppressive properties that reduce inflammation in injured tissue. As such, they could be used to modulate the secondary mechanisms of injury and halt the progression of the secondary insult in the brain after injury. Particularly, MSCs are capable of secreting growth factors that facilitate the regrowth of neurons in the brain. The relative abundance of harvest sources of MSCs also makes them particularly appealing. Recently, numerous studies have investigated the effects of infusion of MSCs into animal models of TBI. The results have shown significant improvement in the motor function of the damaged brain tissues. In this review, we summarize the recent advances in the application of MSCs in the treatment of TBI. The review starts with a brief introduction of the pathophysiology of TBI, followed by the biology of MSCs, and the application of MSCs in TBI treatment. The challenges associated with the application of MSCs in the treatment of TBI and strategies to address those challenges in the future have also been discussed. PMID:28265255

  3. Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

    PubMed

    Hasan, Anwarul; Deeb, George; Rahal, Rahaf; Atwi, Khairallah; Mondello, Stefania; Marei, Hany Elsayed; Gali, Amr; Sleiman, Eliana

    2017-01-01

    Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge potential for application in the treatment of TBI. MSCs have immunosuppressive properties that reduce inflammation in injured tissue. As such, they could be used to modulate the secondary mechanisms of injury and halt the progression of the secondary insult in the brain after injury. Particularly, MSCs are capable of secreting growth factors that facilitate the regrowth of neurons in the brain. The relative abundance of harvest sources of MSCs also makes them particularly appealing. Recently, numerous studies have investigated the effects of infusion of MSCs into animal models of TBI. The results have shown significant improvement in the motor function of the damaged brain tissues. In this review, we summarize the recent advances in the application of MSCs in the treatment of TBI. The review starts with a brief introduction of the pathophysiology of TBI, followed by the biology of MSCs, and the application of MSCs in TBI treatment. The challenges associated with the application of MSCs in the treatment of TBI and strategies to address those challenges in the future have also been discussed.

  4. Isolation and cultivation of stem cells from adult mouse testes.

    PubMed

    Guan, Kaomei; Wolf, Frieder; Becker, Alexander; Engel, Wolfgang; Nayernia, Karim; Hasenfuss, Gerd

    2009-01-01

    The successful isolation and cultivation of spermatogonial stem cells (SSCs) as well as induction of SSCs into pluripotent stem cells will allow us to study their biological characteristics and their applications in therapeutic approaches. Here we provide step-by-step procedures on the basis of previous work in our laboratory for: the isolation of testicular cells from adolescent mice by a modified enzymatic procedure; the enrichment of undifferentiated spermatogonia by laminin selection or genetic selection using Stra8-EGFP (enhanced green fluorescent protein) transgenic mice; the cultivation and conversion of undifferentiated spermatogonia into embryonic stem-like cells, so-called multipotent adult germline stem cells (maGSCs); and characterization of these cells. Normally, it will take about 16 weeks to obtain stable maGSC lines starting from the isolation of testicular cells.

  5. Small molecule-based approaches to adult stem cell therapies.

    PubMed

    Lairson, Luke L; Lyssiotis, Costas A; Zhu, Shoutian; Schultz, Peter G

    2013-01-01

    There is considerable interest in the development of stem cell-based strategies for the treatment of a broad range of human diseases, including neurodegenerative, autoimmune, cardiovascular, and musculoskeletal diseases. To date, such regenerative approaches have focused largely on the development of cell transplantation therapies using cells derived from pluripotent embryonic stem cells (ESCs). Although there have been exciting preliminary reports describing the efficacy of ESC-derived replacement therapies, approaches involving ex vivo manipulated ESCs are hindered by issues of mutation, immune rejection, and ethical controversy. An alternative approach involves direct in vivo modulation or ex vivo expansion of endogenous adult stem cell populations using drug-like small molecules. Here we describe chemical approaches to the regulation of somatic stem cell biology that are yielding new biological insights and that may ultimately lead to innovative new medicines.

  6. Experience-Dependent Neural Plasticity in the Adult Damaged Brain

    ERIC Educational Resources Information Center

    Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

    2011-01-01

    Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper…

  7. Brain tissue banking for stem cells for our future

    PubMed Central

    Palmero, Emily; Palmero, Sheryl; Murrell, Wayne

    2016-01-01

    In our lab we study neurogenesis and the development of brain tumors. We work towards treatment strategies for glioblastoma and towards using autologous neural stem cells for tissue regeneration strategies for brain damage and neurodegenerative disorders. It has been our policy to try to establish living cell cultures from all human biopsy material that we obtain. We hypothesized that small pieces of brain tissue could be cryopreserved and that live neural stem cells could be recovered at a later time. DMSO has been shown to possess a remarkable ability to diffuse through cell membranes and pass into cell interiors. Its chemical properties prevent the formation of damaging ice crystals thus allowing cell storage at or below −180 C. We report here a protocol for successful freezing of small pieces of tissue derived from human brain and human brain tumours. Virtually all specimens could be successfully revived. Assays of phenotype and behaviour show that the cell cultures derived were equivalent to those cultures previously derived from fresh tissue. PMID:27991551

  8. Positron Emission Tomography Using Fluorine F 18 EF5 to Find Oxygen in Tumor Cells of Patients Who Are Undergoing Surgery or Biopsy for Newly Diagnosed Brain Tumors

    ClinicalTrials.gov

    2013-01-15

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Meningeal Melanocytoma

  9. [Brain stem auditory evoked potentials in brain death state].

    PubMed

    Kojder, I; Garell, S; Włodarczyk, E; Sagan, L; Jezewski, D; Slósarek, J

    1998-01-01

    The authors studied auditory brainstem evoked potentials (BAEP) in 27 organ donors aged 40 to 68 years treated in neurosurgery units in Szczecin and Grenoble. Abnormal results were found in all cases. In 63% of cases no evoked action potentials were obtained, in 34% only the 1st wave was obtained, and in two cases evolution was observed with activity extinction. The authors believe that in the process of shaping of BAEP morphotic extinction begins from the later waves to earlier ones in agreement with the rostrocaudal direction of extinction of the functions or brain midline structures, and in a single study various findings may be obtained.

  10. Effect of prenatal lignocaine on auditory brain stem evoked response.

    PubMed Central

    Bozynski, M E; Schumacher, R E; Deschner, L S; Kileny, P

    1989-01-01

    To test the hypothesis that there would be a positive correlation between the interpeak wave (I-V) interval as measured by auditory brain stem evoked response and the ratio of umbilical cord blood arterial to venous lignocaine concentrations in infants born after maternal epidural anaesthesia, 10 normal infants born at full term by elective caesarean section were studied. Umbilical cord arterial and venous plasma samples were assayed for lignocaine, and auditory brain stem evoked responses were elicited at 35 and 70 dB at less than 4 (test 1) and greater than or equal to 48 hours (test 2). Mean wave I-V intervals were prolonged in test 1 when compared with test 2. Linear regression showed the arterial:venous ratio accounted for 66% (left ear) and 43% (right ear) of the variance in test 1 intervals. No association was found in test 2. In newborn infants, changes in serial auditory brain stem evoked response tests occur after maternal lignocaine epidural anaesthesia and these changes correlate with blood lignocaine concentrations. PMID:2774635

  11. Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

    PubMed Central

    Seekaew, Pich

    2016-01-01

    Abstract Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It was previously shown that traumatic brain injury (TBI) stimulated neural stem cell (NSC) proliferation in the adult hippocampus, indicating an innate repair mechanism, but it is unknown how TBI promotes NSC proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice with TBI from controlled cortical impact (CCI). The peak of mTORC1 activation in the hippocampal subgranular zone, where NSCs reside, is 24–48 h after trauma, correlating with the peak of TBI-enhanced NSC proliferation. By use of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, we found that TBI activated mTORC1 in NSCs. With 5-bromo-2′-deoxyuridine labeling, we observed that TBI increased mTORC1 activation in proliferating NSCs. Furthermore, administration of rapamycin abolished TBI-promoted NSC proliferation. Taken together, these data indicate that mTORC1 activation is required for NSC proliferation postinjury, and thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair after TBI. PMID:27822507

  12. Neural stem cell-based gene therapy for brain tumors.

    PubMed

    Kim, Seung U

    2011-03-01

    Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate in patients suffering from these brain tumors; however, it remains incurable in large proportion of patients. Therefore, there is substantial need for effective, low-toxicity therapies for patients with malignant brain tumors, and gene therapy targeting brain tumors should fulfill this requirement. Gene therapy for brain tumors includes many therapeutic strategies and these strategies can be grouped in two major categories: molecular and immunologic. The widely used molecular gene therapy approach is suicide gene therapy based on the conversion of non-toxic prodrugs into active anticancer agents via introduction of enzymes and genetic immunotherapy involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and TRAIL. For both molecular and immune gene therapy, neural stem cells (NSCs) can be used as delivery vehicle of therapeutic genes. NSCs possess an inherent tumor tropism that supports their use as a reliable delivery vehicle to target therapeutic gene products to primary brain tumors and metastatic cancers throughout the brain. Significance of the NSC-based gene therapy for brain tumor is that it is possible to exploit the tumor-tropic property of NSCs to mediate effective, tumor-selective therapy for primary and metastatic cancers in the brain and outside, for which no tolerated curative treatments are currently available.

  13. Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage.

    PubMed

    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.

  14. Defining a developmental path to neural fate by global expression profiling of mouse embryonic stem cells and adult neural stem/progenitor cells.

    PubMed

    Aiba, Kazuhiro; Sharov, Alexei A; Carter, Mark G; Foroni, Chiara; Vescovi, Angelo L; Ko, Minoru S H

    2006-04-01

    To understand global features of gene expression changes during in vitro neural differentiation, we carried out the microarray analysis of embryonic stem cells (ESCs), embryonal carcinoma cells, and adult neural stem/progenitor (NS) cells. Expression profiling of ESCs during differentiation in monolayer culture revealed three distinct phases: undifferentiated ESCs, primitive ectoderm-like cells, and neural progenitor cells. Principal component (PC) analysis revealed that these cells were aligned on PC1 over the course of 6 days. This PC1 represents approximately 4,000 genes, the expression of which increased with neural commitment/differentiation. Furthermore, NS cells derived from adult brain and their differentiated cells were positioned along this PC axis further away from undifferentiated ESCs than embryonic stem-derived neural progenitors. We suggest that this PC1 defines a path to neural fate, providing a scale for the degree of commitment/differentiation.

  15. Haploidentical Stem Cell Transplantation in Adult Haematological Malignancies

    PubMed Central

    Parmesar, Kevon; Raj, Kavita

    2016-01-01

    Haematopoietic stem cell transplantation is a well-established treatment option for both hematological malignancies and nonmalignant conditions such as aplastic anemia and haemoglobinopathies. For those patients lacking a suitable matched sibling or matched unrelated donor, haploidentical donors are an alternative expedient donor pool. Historically, haploidentical transplantation led to high rates of graft rejection and GVHD. Strategies to circumvent these issues include T cell depletion and management of complications thereof or T replete transplants with GVHD prophylaxis. This review is an overview of these strategies and contemporaneous outcomes for hematological malignancies in adult haploidentical stem cell transplant recipients. PMID:27313619

  16. Stem Cells for Ischemic Brain Injury: A Critical Review

    PubMed Central

    Burns, Terry C.; Verfaillie, Catherine M.; Low, Walter C.

    2014-01-01

    No effective therapy is currently available to promote recovery following ischemic stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. We undertook a detailed review of data from recent basic science and preclinical studies to investigate the potential application of endogenous and exogenous stem cell therapies for treatment of cerebral ischemia. To date, spontaneous endogenous neurogenesis has been observed in response to ischemic injury, and can be enhanced via infusion of appropriate cytokines. Exogenous stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells from multiple sources cells also exhibit neuroprotective properties that may ameliorate stroke deficits. In many cases, functional benefits observed are likely independent of neural differentiation, though exact mechanisms remain poorly understood. Future studies of neuroregeneration will require the demonstration of function in endogenously born neurons following focal ischemia. Further, methods are currently lacking to definitively demonstrate the therapeutic effect of newly introduced neural cells. Increased plasticity following stroke may facilitate the functional integration of new neurons, but the loss of appropriate guidance cues and supporting architecture in the infarct cavity will likely impede the restoration of lost circuitry. As such careful investigation of the mechanisms underlying trophic benefits will be essential. Evidence to date suggest that continued development of stem cell therapies may ultimately lead to viable treatment options for ischemic brain injury. PMID:19399885

  17. Adult neurogenesis, neural stem cells and Alzheimer's disease: developments, limitations, problems and promises.

    PubMed

    Taupin, Philippe

    2009-12-01

    Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease, leading to severe incapacity and death. It is the most common form of dementia among older people. AD is characterized in the brain by amyloid plaques, neurofibrillary tangles, neuronal degeneration, aneuploidy and enhanced neurogenesis and by cognitive, behavioral and physical impairments. Inherited mutations in several genes and genetic, acquired and environmental risk factors have been reported as causes for developing the disease, for which there is currently no cure. Current treatments for AD involve drugs and occupational therapies, and future developments involve early diagnosis and stem cell therapy. In this manuscript, we will review and discuss the recent developments, limitations, problems and promises on AD, particularly related to aneuploidy, adult neurogenesis, neural stem cells (NSCs) and cellular therapy. Though adult neurogenesis may be beneficial for regeneration of the nervous system, it may underly the pathogenesis of AD. Cellular therapy is a promising strategy for AD. Limitations in protocols to establish homogeneous populations of neural progenitor and stem cells and niches for neurogenesis need to be resolved and unlocked, for the full potential of adult NSCs to be realized for therapy.

  18. Mechanisms of neuronal migration in the adult brain.

    PubMed

    Kaneko, Naoko; Sawada, Masato; Sawamoto, Kazunobu

    2017-03-02

    Adult neurogenesis was first observed nearly 60 years ago, and it has since grown into an important neurochemistry research field. Much recent research has focused on the treatment of brain diseases through neuronal regeneration with endogenously generated neurons. In the adult brain, immature neurons called neuroblasts are continuously generated in the ventricular-subventricular zone (V-SVZ). These neuroblasts migrate rapidly through the rostral migratory stream to the olfactory bulb, where they mature and are integrated into the neuronal circuitry. After brain insult, some of the neuroblasts in the V-SVZ migrate toward the lesion to repopulate the injured tissue. This notable migratory capacity of V-SVZ-derived neuroblasts is important for efficiently regenerating neurons in remote areas of the brain. As these neurons migrate for long distances through adult brain tissue, they are supported by various guidance cues and structures that act as scaffolds. Some of these mechanisms are unique to neuroblast migration in the adult brain, and are not involved in migration in the developing brain. Here, we review the latest findings on the mechanisms of neuroblast migration in the adult brain under physiological and pathological conditions, and discuss various issues that still need to be resolved. This article is protected by copyright. All rights reserved.

  19. Pericytes, integral components of adult hematopoietic stem cell niches.

    PubMed

    Sá da Bandeira, D; Casamitjana, J; Crisan, M

    2017-03-01

    The interest in perivascular cells as a niche for adult hematopoietic stem cells (HSCs) is significantly growing. In the adult bone marrow (BM), perivascular cells and HSCs cohabit. Among perivascular cells, pericytes are precursors of mesenchymal stem/stromal cells (MSCs) that are capable of differentiating into osteoblasts, adipocytes and chondrocytes. In situ, pericytes are recognised by their localisation to the abluminal side of the blood vessel wall and closely associated with endothelial cells, in combination with the expression of markers such as CD146, neural glial 2 (NG2), platelet derived growth factor receptor β (PDGFRβ), α-smooth muscle actin (α-SMA), nestin (Nes) and/or leptin receptor (LepR). However, not all pericytes share a common phenotype: different immunophenotypes can be associated with distinct mesenchymal features, including hematopoietic support. In adult BM, arteriolar and sinusoidal pericytes control HSC behaviour, maintenance, quiescence and trafficking through paracrine effects. Different groups identified and characterized hematopoietic supportive pericyte subpopulations using various markers and mouse models. In this review, we summarize recent work performed by others to understand the role of the perivascular niche in the biology of HSCs in adults, as well as their importance in the development of therapies.

  20. Memory and Brain Volume in Adults Prenatally Exposed to Alcohol

    ERIC Educational Resources Information Center

    Coles, Claire D.; Goldstein, Felicia C.; Lynch, Mary Ellen; Chen, Xiangchuan; Kable, Julie A.; Johnson, Katrina C.; Hu, Xiaoping

    2011-01-01

    The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n = 26; Alcohol-related Neurodevelopmental Disorder, n = 36; and Dysmorphic, n = 30) were imaged using structural MRI with brain volume calculated for…

  1. Childhood Onset Schizophrenia: Cortical Brain Abnormalities as Young Adults

    ERIC Educational Resources Information Center

    Greenstein, Deanna; Lerch, Jason; Shaw, Philip; Clasen, Liv; Giedd, Jay; Gochman, Peter; Rapoport, Judith; Gogtay, Nitin

    2006-01-01

    Background: Childhood onset schizophrenia (COS) is a rare but severe form of the adult onset disorder. While structural brain imaging studies show robust, widespread, and progressive gray matter loss in COS during adolescence, there have been no longitudinal studies of sufficient duration to examine comparability with the more common adult onset…

  2. [Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain].

    PubMed

    Respondek, Michalina; Buszman, Ewa

    2015-12-31

    Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC), which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells.

  3. New Nerve Cells for the Adult Brain.

    ERIC Educational Resources Information Center

    Kempermann, Gerd; Gage, Fred H.

    1999-01-01

    Contrary to dogma, the human brain does produce new nerve cells in adulthood. The mature human brain spawns neurons routinely in the hippocampus, an area important to memory and learning. This research can make it possible to ease any number of disorders involving neurological damage and death. (CCM)

  4. Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells.

    PubMed

    Deng, Peter; Torrest, Audrey; Pollock, Kari; Dahlenburg, Heather; Annett, Geralyn; Nolta, Jan A; Fink, Kyle D

    2016-05-01

    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.

  5. 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

  6. Growth and differentiation of adult hippocampal arctic ground squirrel neural stem cells.

    PubMed

    Drew, Kelly L; McGee, Rebecca C; Wells, Matthew S; Kelleher-Andersson, Judith A

    2011-01-07

    Arctic ground squirrels (Urocitellus parryii, AGS) are unique in their ability to hibernate with a core body temperature near or below freezing. These animals also resist ischemic injury to the brain in vivo and oxygen-glucose deprivation in vitro. These unique qualities provided the impetus to isolate AGS neurons to examine inherent neuronal characteristics that could account for the capacity of AGS neurons to resist injury and cell death caused by ischemia and extremely cold temperatures. Identifying proteins or gene targets that allow for the distinctive properties of these cells could aid in the discovery of effective therapies for a number of ischemic indications and for the study of cold tolerance. Adult AGS hippocampus contains neural stem cells that continue to proliferate, allowing for easy expansion of these stem cells in culture. We describe here methods by which researchers can utilize these stem cells and differentiated neurons for any number of purposes. By closely following these steps the AGS neural stem cells can be expanded through two passages or more and then differentiated to a culture high in TUJ1-positive neurons (~50%) without utilizing toxic chemicals to minimize the number of dividing cells. Ischemia induces neurogenesis and neurogenesis which proceeds via MEK/ERK and PI3K/Akt survival signaling pathways contributes to ischemia resistance in vivo and in vitro (Kelleher-Anderson, Drew et al., in preparation). Further characterization of these unique neural cells can advance on many fronts, using some or all of these methods.

  7. Tumourigenicity and Immunogenicity of Induced Neural Stem Cell Grafts Versus Induced Pluripotent Stem Cell Grafts in Syngeneic Mouse Brain

    PubMed Central

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

    2016-01-01

    Along with the development of stem cell-based therapies for central nervous system (CNS) disease, the safety of stem cell grafts in the CNS, such as induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs), should be of primary concern. To provide scientific basis for evaluating the safety of these stem cells, we determined their tumourigenicity and immunogenicity in syngeneic mouse brain. Both iPSCs and embryonic stem cells (ESCs) were able to form tumours in the mouse brain, leading to tissue destruction along with immune cell infiltration. In contrast, no evidence of tumour formation, brain injury or immune rejection was observed with iNSCs, neural stem cells (NSCs) or mesenchymal stem cells (MSCs). With the help of gene ontology (GO) enrichment analysis, we detected significantly elevated levels of chemokines in the brain tissue and serum of mice that developed tumours after ESC or iPSC transplantation. Moreover, we also investigated the interactions between chemokines and NF-κB signalling and found that NF-κB activation was positively correlated with the constantly rising levels of chemokines, and vice versa. In short, iNSC grafts, which lacked any resulting tumourigenicity or immunogenicity, are safer than iPSC grafts. PMID:27417157

  8. Bone marrow-derived stem cell therapy for metastatic brain cancers.

    PubMed

    Kaneko, Yuji; Tajiri, Naoki; Staples, Meaghan; Reyes, Stephanny; Lozano, Diego; Sanberg, Paul R; Freeman, Thomas B; van Loveren, Harry; Kim, Seung U; Borlongan, Cesar V

    2015-01-01

    We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

  9. Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain

    PubMed Central

    Sun, Gerald J.; Zhou, Yi; Stadel, Ryan P.; Moss, Jonathan; Yong, Jing Hui A.; Ito, Shiori; Kawasaki, Nicholas K.; Phan, Alexander T.; Oh, Justin H.; Modak, Nikhil; Reed, Randall R.; Toni, Nicolas; Song, Hongjun; Ming, Guo-li

    2015-01-01

    In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial “whole-mount” dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system. PMID:26170290

  10. Novel Adult Stem Cells for Peripheral Nerve Regeneration

    DTIC Science & Technology

    2012-09-01

    Circulation 103, 882–888 (2001). 52. Biernaskie, J. et al. SKPs derive from hair follicle precursors and exhibit properties of adult dermal stem cells...3). * indicates significant difference between indicated groups using Holm’s t- test . (P < 0.01). (l–s) Immunostaining of isolated sm-mHC − cells...and the tissue from which the cells were derived using student’s t- test (P < 0.05). † indicates significant difference between inferior vena cava and

  11. Effects of environmental tobacco smoke on adult rat brain biochemistry.

    PubMed

    Fuller, Brian F; Gold, Mark S; Wang, Kevin K W; Ottens, Andrew K

    2010-05-01

    Environmental tobacco smoke (ETS) has been linked to deleterious health effects, particularly pulmonary and cardiac disease; yet, the general public considers ETS benign to brain function in adults. In contrast, epidemiological data have suggested that ETS impacts the brain and potentially modulates neurodegenerative disease. The present study begins to examine yet unknown biochemical effects of ETS on the adult mammalian brain. In the developed animal model, adult male rats were exposed to ETS 3 h a day for 3 weeks. Biochemical data showed altered glial fibrillary acid protein levels as a main treatment effect of ETS, suggestive of reactive astrogliosis. Yet, markers of oxidative and cell stress were unaffected by ETS exposure in the brain regions examined. Increased proteolytic degradation of alphaII-spectrin by caspase-3 and the dephosphorylation of serine(116) on PEA-15 indicated greater apoptotic cell death modulated by the extrinsic pathway in the brains of ETS-exposed animals. Further, beta-synuclein was upregulated by ETS, a neuroprotective protein previously reported to exhibit anti-apoptotic and anti-fibrillogenic properties. These findings demonstrate that ETS exposure alters the neuroproteome of the adult rat brain, and suggest modulation of inflammatory and cell death processes.

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

    PubMed Central

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

    2016-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.19735.001 PMID:27864883

  13. Differentiated human stem cells resemble fetal, not adult, β cells.

    PubMed

    Hrvatin, Sinisa; O'Donnell, Charles W; Deng, Francis; Millman, Jeffrey R; Pagliuca, Felicia Walton; DiIorio, Philip; Rezania, Alireza; Gifford, David K; Melton, Douglas A

    2014-02-25

    Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorted insulin-expressing (INS(+)) cells derived from three independent hPSC lines, human fetal pancreata, and adult human islets points to two major conclusions: (i) Different hPSC lines produce highly similar INS(+) cells and (ii) hPSC-derived INS(+) (hPSC-INS(+)) cells more closely resemble human fetal β cells than adult β cells. This study provides a direct comparison of transcriptional programs between pure hPSC-INS(+) cells and true β cells and provides a catalog of genes whose manipulation may convert hPSC-INS(+) cells into functional β cells.

  14. Positional identity of adult stem cells in salamander limb regeneration.

    PubMed

    Kumar, Anoop; Gates, Phillip B; Brockes, Jeremy P

    2007-01-01

    Limb regeneration in larval and adult salamanders proceeds from a mound of mesenchymal stem cells called the limb blastema. The blastema gives rise just to those structures distal to its level of origin, and this property of positional identity is reset to more proximal values by treatment with retinoic acid. We have identified a cell surface protein, called Prod1/CD59, which appears to be a determinant of proximodistal identity. Prod1 is expressed in an exponential gradient in an adult limb as determined by detection of both mRNA and immunoreactive protein. Prod1 protein is up-regulated after treatment of distal blastemas with RA and this is particularly marked in cells of the dermis. These cells have previously been implicated in pattern formation during limb regeneration.

  15. Neural stem cells harvested from live brains by antibody-conjugated magnetic nanoparticles.

    PubMed

    Lui, C N P; Tsui, Y P; Ho, A S L; Shum, D K Y; Chan, Y S; Wu, C T; Li, H W; Tsang, S C Edman; Yung, K K L

    2013-11-18

    It stems from the magnetism: The extraction of stem/progenitor cells from the brain of live animals is possible using antibodies conjugated to magnetic nanoparticles (Ab-MNPs). The Ab-MNPs are introduced to a rat's brain with a superfine micro-syringe. The stem cells attach to the Ab-MNPs and are magnetically isolated and removed. They can develop into neurospheres and differentiate into different types of cells outside the subject body. The rat remains alive and healthy.

  16. Spatial distribution and cellular composition of adult brain proliferative zones in the teleost, Gymnotus omarorum

    PubMed Central

    Olivera-Pasilio, Valentina; Peterson, Daniel A.; Castelló, María E.

    2014-01-01

    Proliferation of stem/progenitor cells during development provides for the generation of mature cell types in the CNS. While adult brain proliferation is highly restricted in the mammals, it is widespread in teleosts. The extent of adult neural proliferation in the weakly electric fish, Gymnotus omarorum has not yet been described. To address this, we used double thymidine analog pulse-chase labeling of proliferating cells to identify brain proliferation zones, characterize their cellular composition, and analyze the fate of newborn cells in adult G. omarorum. Short thymidine analog chase periods revealed the ubiquitous distribution of adult brain proliferation, similar to other teleosts, particularly Apteronotus leptorhynchus. Proliferating cells were abundant at the ventricular-subventricular lining of the ventricular-cisternal system, adjacent to the telencephalic subpallium, the diencephalic preoptic region and hypothalamus, and the mesencephalic tectum opticum and torus semicircularis. Extraventricular proliferation zones, located distant from the ventricular-cisternal system surface, were found in all divisions of the rombencephalic cerebellum. We also report a new adult proliferation zone at the caudal-lateral border of the electrosensory lateral line lobe. All proliferation zones showed a heterogeneous cellular composition. The use of short (24 h) and long (30 day) chase periods revealed abundant fast cycling cells (potentially intermediate amplifiers), sparse slow cycling (potentially stem) cells, cells that appear to have entered a quiescent state, and cells that might correspond to migrating newborn neural cells. Their abundance and migration distance differed among proliferation zones: greater numbers and longer range and/or pace of migrating cells were associated with subpallial and cerebellar proliferation zones. PMID:25249943

  17. The effects of vitamin D on brain development and adult brain function.

    PubMed

    Kesby, James P; Eyles, Darryl W; Burne, Thomas H J; McGrath, John J

    2011-12-05

    A role for vitamin D in brain development and function has been gaining support over the last decade. Multiple lines of evidence suggest that this vitamin is actually a neuroactive steroid that acts on brain development, leading to alterations in brain neurochemistry and adult brain function. Early deficiencies have been linked with neuropsychiatric disorders, such as schizophrenia, and adult deficiencies have been associated with a host of adverse brain outcomes, including Parkinson's disease, Alzheimer's disease, depression and cognitive decline. This review summarises the current state of research on the actions of vitamin D in the brain and the consequences of deficiencies in this vitamin. Furthermore, we discuss specific implications of vitamin D status on the neurotransmitter, dopamine.

  18. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.

    PubMed

    Ryu, Sun; Lee, Seung-Hoon; Kim, Seung U; Yoon, Byung-Woo

    2016-02-01

    Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2'-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2'-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.

  19. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Adult stem cells for cardiac repair: a choice between skeletal myoblasts and bone marrow stem cells.

    PubMed

    Ye, Lei; Haider, Husnain Kh; Sim, Eugene K W

    2006-01-01

    The real promise of a stem cell-based approach for cardiac regeneration and repair lies in the promotion of myogenesis and angiogenesis at the site of the cell graft to achieve both structural and functional benefits. Despite all of the progress and promise in this field, many unanswered questions remain; the answers to these questions will provide the much-needed breakthrough to harness the real benefits of cell therapy for the heart in the clinical perspective. One of the major issues is the choice of donor cell type for transplantation. Multiple cell types with varying potentials have been assessed for their ability to repopulate the infarcted myocardium; however, only the adult stem cells, that is, skeletal myoblasts (SkM) and bone marrow-derived stem cells (BMC), have been translated from the laboratory bench to clinical use. Which of these two cell types will provide the best option for clinical application in heart cell therapy remains arguable. With results pouring in from the long-term follow-ups of previously conducted phase I clinical studies, and with the onset of phase II clinical trials involving larger population of patients, transplantation of stem cells as a sole therapy without an adjunct conventional revascularization procedure will provide a deeper insight into the effectiveness of this approach. The present article discusses the pros and cons of using SkM and BMC individually or in combination for cardiac repair, and critically analyzes the progress made with each cell type.

  1. Activin and TGF-β effects on brain development and neural stem cells.

    PubMed

    Rodríguez-Martínez, Griselda; Velasco, Iván

    2012-11-01

    Transforming Growth Factor-β (TGF-β) family members are ubiquitously expressed, participating in the regulation of many processes in different cell types both in embryonic and adult stages. Several members of this family, including Activins, TGF-β1-3 and Nodal, have been implicated in the development and maintenance of various organs, in which stem cells play important roles. Although TGF-β was initially considered an injury-related cytokine, it became clear that not only TGF-β, but other members of this family, play critical roles in morphogenesis and cell lineage specification. During brain development, Activin and TGF-βs as well as their cognate receptors, are expressed in different patterns. The roles of Activin and TGF-β during CNS development are sometimes contradictory, because these proteins present different actions depending on the cell type and the context. The aim of this review is to summarize current information on the actions of TGF-β members during developing brain, and also on Neural Stem/Progenitor Cells (NSPC). We focus on the TGF-β subgroup, specifically on the effects of TGF-β1 and Activin A. In the first section we describe the main characteristics of the ligands, its receptors as well as the proteins and mechanisms involved in signaling. Next, we discuss the main advances concerning TGF-β1 and Activin actions during brain development and their roles in NSPC fate decision and neuroprotection both in vitro and in vivo. The emerging picture from these studies suggests that these growth factors can be used to manipulate neurogenesis and might help to achieve restoration after brain deterioration.

  2. From adult stem cells to cancer stem cells: Oct-4 Gene, cell-cell communication, and hormones during tumor promotion.

    PubMed

    Trosko, James E

    2006-11-01

    Carcinogenesis is characterized by "initiation," "promotion," and "progression" phases. The "stem cell theory" and "de-differentiation" theories are used to explain the origin of cancer. Growth control for stem cells, which lack functional gap junctional intercellular communication (GJIC), involves negative soluble or niche factors, while for progenitor cells, it involves GJIC. Tumor promoters, hormones, and growth factors inhibit GJIC reversibly. Oncogenes stably inhibit GJIC. Cancer cells, which lack growth control and the ability to terminally differentiate and to apoptose, lack GJIC. The Oct3/4 gene, a POU (Pit-Oct-Unc) family of transcription factors was thought to be expressed only in embryonic stem cells and in tumor cells. With the availability of normal adult human stem cells, tests for the expression of Oct3/4 gene and the stem cell theory in human carcinogenesis became possible. Human breast, liver, pancreas, kidney, mesenchyme, and gastric stem cells, HeLa and MCF-7 cells, and canine tumors were tested with antibodies and polymerase chain reaction (PCR) primers for Oct3/4. Adult human breast stem cells, immortalized nontumorigenic and tumor cell lines, but not the normal differentiated cells, expressed Oct3/4. Adult human differentiated cells lose their Oct-4 expression. Oct3/4 is expressed in a few cells found in the basal layer of human skin epidermis. The data demonstrate that normal adult stem cells and cancer stem cells maintain expression of Oct3/4, consistent with the stem cell hypothesis of carcinogenesis. These Oct-4 positive cells might represent the "cancer stem cells." A strategy to target "cancer stem cells" is to suppress the Oct-4 gene in order to cause the cells to differentiate.

  3. Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis.

    PubMed

    Tai, Mei-Hui; Chang, Chia-Cheng; Kiupel, Matti; Webster, Joshua D; Olson, L Karl; Trosko, James E

    2005-02-01

    The Oct3/4 gene, a POU family transcription factor, has been noted as being specifically expressed in embryonic stem cells and in tumor cells but not in cells of differentiated tissues. With the ability to isolate adult human stem cells it became possible to test for the expression of Oct3/4 gene in adult stem cells and to test the stem cell theory of carcinogenesis. Using antibodies and PCR primers we tested human breast, liver, pancreas, kidney, mesenchyme and gastric stem cells, the cancer cell lines HeLa and MCF-7 and human, dog and rat tumors for Oct4 expression. The results indicate that adult human stem cells, immortalized non-tumorigenic cells and tumor cells and cell lines, but not differentiated cells, express Oct4. Oct4 is expressed in a few cells found in the basal layer of human skin epidermis. The data demonstrate that adult stem cells maintain expression of Oct4, consistent with the stem cell hypothesis of carcinogenesis.

  4. Behavior of neural stem cells in the Alzheimer brain.

    PubMed

    Waldau, B; Shetty, A K

    2008-08-01

    Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid peptides (Abeta) and a progressive loss of neurons leading to dementia. Because hippocampal neurogenesis is linked to functions such as learning, memory and mood, there has been great interest in examining the effects of AD on hippocampal neurogenesis. This article reviews the pertinent studies and tries to unite them in one possible disease model. Early in the disease, oligomeric Abeta may transiently promote the generation of immature neurons from neural stem cells (NSCs). However, reduced concentrations of multiple neurotrophic factors and higher levels of fibroblast growth factor-2 seem to induce a developmental arrest of newly generated neurons. Furthermore, fibrillary Abeta and down-regulation of oligodendrocyte-lineage transcription factor-2 (OLIG2) may cause the death of these nonfunctional neurons. Therefore, altering the brain microenvironment for fostering apt maturation of graft-derived neurons may be critical for improving the efficacy of NSC transplantation therapy for AD.

  5. Adult Bone Marrow Neural Crest Stem Cells and Mesenchymal Stem Cells Are Not Able to Replace Lost Neurons in Acute MPTP-Lesioned Mice

    PubMed Central

    Neirinckx, Virginie; Marquet, Alice; Coste, Cécile

    2013-01-01

    Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC) or mesenchymal stem cells (MSC) survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management. PMID:23741377

  6. Brain abscess caused by Citrobacter koseri infection in an adult.

    PubMed

    Liu, Heng-Wei; Chang, Chih-Ju; Hsieh, Cheng-Ta

    2015-04-01

    Citrobacter koseri is a gram-negative bacillus that causes mostly meningitis and brain abscesses in neonates and infants. However, brain abscess caused by Citrobacter koseri infection in an adult is extremely rare, and only 2 cases have been described. Here, we reported a 73-year-old male presenting with a 3-week headache. A history of diabetes mellitus was noted. The images revealed a brain abscess in the left frontal lobe and pus culture confirmed the growth of Citrobacter koseri. The clinical symptoms improved completely postoperatively.

  7. Inflammation is detrimental for neurogenesis in adult brain

    NASA Astrophysics Data System (ADS)

    Ekdahl, Christine T.; Claasen, Jan-Hendrik; Bonde, Sara; Kokaia, Zaal; Lindvall, Olle

    2003-11-01

    New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation.

  8. FACS purification of immunolabeled cell types from adult rat brain.

    PubMed

    Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G; Picciotto, Marina R; Hope, Bruce T

    2012-01-15

    Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience.

  9. Sources of variability in auditory brain stem evoked potential measures over time.

    PubMed

    Edwards, R M; Buchwald, J S; Tanguay, P E; Schwafel, J A

    1982-02-01

    Auditory brain stem EPs elicited in 10 normal adults by monaural clicks delivered at 72 dB HL, 20/sec showed no significant change in wave latencies or in the ratio of wave I to wave Y amplitude across 250 trial subsets, across 250 trial subsets, across 1500 trial blocks within a test session, or across two test sessions separated by several months. Sources of maximum variability were determined by using mean squared differences with all but one condition constant. 'Subjects' was shown to contribute the most variability followed by 'ears', 'sessions' and 'runs'; collapsing across conditions, wave III latencies were found to be the least variable, while wave II showed the most variability. Some EP morphologies showed extra peaks between waves II and IV, missing wave IV or wave IV fused with wave V. Such variations in wave form morphology were independent of EMG amplitude and were characteristic of certain individuals.

  10. Visualization of adult stem cells within their niches using the Drosophila germline as a model system.

    PubMed

    König, Annekatrin; Shcherbata, Halyna R

    2013-01-01

    The germaria of the fruit fly Drosophila melanogaster present an excellent model to study germline stem cell-niche interactions. Two to three adult stem cells are surrounded by a number of somatic cells that form the niche. Here we describe how Drosophilae germaria can be dissected and specifically immuno-stained to allow for identification and analysis of both the adult stem cells and their somatic niche cells.

  11. Perivascular instruction of cell genesis and fate in the adult brain.

    PubMed

    Goldman, Steven A; Chen, Zhuoxun

    2011-10-26

    The perivascular niche for neurogenesis was first reported as the co-association of newly generated neurons and their progenitors with both dividing and mitotically quiescent endothelial cells in restricted regions of the brain in adult birds and mammals alike. This review attempts to summarize our present understanding of the interaction of blood vessels with neural stem and progenitor cells, addressing both glial and neuronal progenitor cell interactions in the perivascular niche. We review the molecular interactions that are most critical to the endothelial control of stem and progenitor cell mobilization and differentiation. The focus throughout will be on defining those perivascular ligand-receptor interactions shared among these systems, as well as those that clearly differ as a function of cell type and setting, by which specificity may be achieved in the development of targeted therapeutics.

  12. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury.

    PubMed

    Anbari, Fatemeh; Khalili, Mohammad Ali; Bahrami, Ahmad Reza; Khoradmehr, Arezoo; Sadeghian, Fatemeh; Fesahat, Farzaneh; Nabi, Ali

    2014-05-01

    To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 10(6) rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

  13. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury

    PubMed Central

    Anbari, Fatemeh; Khalili, Mohammad Ali; Bahrami, Ahmad Reza; Khoradmehr, Arezoo; Sadeghian, Fatemeh; Fesahat, Farzaneh; Nabi, Ali

    2014-01-01

    To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 106 rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells. PMID:25206912

  14. Long-term tracing of the BrdU label-retaining cells in adult rat brain.

    PubMed

    Zhang, Lei; Li, Haihong; Zeng, Shaopeng; Chen, Lu; Fang, Zeman; Huang, Qingjun

    2015-03-30

    Stem cells have been shown to be label-retaining, slow-cycling cells. In the adult mammalian central nervous system, the distribution of the stem cells is inconsistent among previous studies. The purpose of the present study was to determine the distribution of BrdU-LRCs and the cell types of the BrdU-LRCs in rat brain. To label BrdU-LRCs in rat brain, six newborn rats were administered intraperitoneal injections of BrdU 50mg/kg/time twice a day at 2h intervals, over four consecutive days. The BrdU-LRCs were detected by immunohistochemistry, the cell types were examined by double immunofluorescence staining for BrdU/GFAP and BrdU/MAP2, and the percentage of BrdU-LRCs was calculated following a chase period of 24 weeks post-injection. We observed that BrdU-LRCs distributed extensively in rat brain. In the LV, DG, striatum, cerebellum and neocortex, the percentage of BrdU-LRCs was 11.3 ± 2.5%, 10.9 ± 1.3%, 6.4 ± 1.2%, 5.6 ± 0.8%, and 4.9 ± 0.6%, respectively. The highest density of BrdU-LRCs was in LV and DG, the known stem cell sites in adult mammalian brain. Both BrdU/GFAP and BrdU/MAP2 double-staining cells could be detected in the above five brain subregions. Ongoing cell production was widespread in the adult mammalian brain, which would allow us to reevaluate the capacity and potentiality of the brain in homeostasis, wound repair, and regeneration.

  15. Drosophila Brat and Human Ortholog TRIM3 Maintain Stem Cell Equilibrium and Suppress Brain Tumorigenesis by Attenuating Notch Nuclear Transport.

    PubMed

    Mukherjee, Subhas; Tucker-Burden, Carol; Zhang, Changming; Moberg, Kenneth; Read, Renee; Hadjipanayis, Costas; Brat, Daniel J

    2016-04-15

    Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. Mutation of a single gene in Drosophila, Brain Tumor (Brat), leads to disrupted asymmetric cell division resulting in dramatic neoplastic proliferation of neuroblasts and massive larval brain overgrowth. To uncover the mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model using brat-RNAi driven by the neuroblast-specific promoter inscuteable Suppressing Brat in this population led to the accumulation of actively proliferating neuroblasts and a lethal brain tumor phenotype. brat-RNAi caused upregulation of Notch signaling, a node critical for self-renewal, by increasing protein expression and enhancing nuclear transport of Notch intracellular domain (NICD). In human glioblastoma, we demonstrated that the human ortholog of Drosophila Brat, tripartite motif-containing protein 3 (TRIM3), similarly suppressed NOTCH1 signaling and markedly attenuated the stem cell component. We also found that TRIM3 suppressed nuclear transport of active NOTCH1 (NICD) in glioblastoma and demonstrated that these effects are mediated by direct binding of TRIM3 to the Importin complex. Together, our results support a novel role for Brat/TRIM3 in maintaining stem cell equilibrium and suppressing tumor growth by regulating NICD nuclear transport. Cancer Res; 76(8); 2443-52. ©2016 AACR.

  16. Bilateral Brain Regions Associated with Naming in Older Adults

    ERIC Educational Resources Information Center

    Obler, Loraine K.; Rykhlevskaia, Elena; Schnyer, David; Clark-Cotton, Manuella R.; Spiro, Avron, III; Hyun, JungMoon; Kim, Dae-Shik; Goral, Mira; Albert, Martin L.

    2010-01-01

    To determine structural brain correlates of naming abilities in older adults, we tested 24 individuals aged 56-79 on two confrontation-naming tests (the Boston Naming Test (BNT) and the Action Naming Test (ANT)), then collected from these individuals structural Magnetic-Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) data. Overall,…

  17. KCTD11 expression in medulloblastoma is lower than in adult cerebellum and higher than in neural stem cells.

    PubMed

    Zawlik, Izabela; Zakrzewska, Magdalena; Witusik, Monika; Golanska, Ewa; Kulczycka-Wojdala, Dominika; Szybka, Malgorzata; Piaskowski, Sylwester; Wozniak, Krystyna; Zakrzewski, Krzysztof; Papierz, Wielislaw; Liberski, Pawel P; Rieske, Piotr

    2006-10-01

    Medulloblastoma (MB) is the most common malignant brain tumor of childhood, and the most frequent associated genetic alteration is loss of heterozygosity on chromosome region 7p13. Two genes mapping to this region, KCTD11 (alias REN) and HIC1, have been proposed as involved in MB pathogenesis. We used real-time polymerase chain reaction in 20 tissue samples of primary MB to examine the transcriptional level of the two genes, with reference to two types of controls: adult cerebellum and fetal neural stem cells. A significant reduction of KCTD11 expression relative to adult normal cerebellum was detected in 14 of 20 (70%) of MB samples. Neural stem cells had even lower levels of KCTD11 expression than did MB. HIC1 gene expression was low ( approximately 100 times lower than KCTD11 expression) in MB, and low also in both adult cerebellum and neural stem cells. Hypermethylation of the 5'UTR or the central region of HIC1 (or both) was detected in a significant number of MB samples, as well as in cerebellum and neural stem cells. Our data suggest that KCTD11 may play an important role in MB tumorigenesis, but do not support the role of HIC1 in this tumor development. We argue that recognition of the gene or genes important in MB tumorigenesis depends in part on defining an appropriate control.

  18. Expression of brain-derived neurotrophic factor in the rat forebrain and upper brain stem during postnatal development: an immunohistochemical study.

    PubMed

    Kim, J K; Jeon, S M; Lee, K M; Park, E S; Cho, H J

    2007-05-25

    The present study was undertaken to characterize the regional and temporal patterns of brain-derived neurotrophic factor (BDNF) in the rat forebrain and upper brain stem during postnatal development using an immunohistochemical approach. Results indicated that BDNF-immunoreactive (IR) cells could be divided into three groups based on their postnatal developmental patterns: (group 1) BDNF-IR cells were first detected between postnatal days (PND) 1 and 7, and thereafter they increased in number and remained stable during later stages of ontogeny; (group 2) BDNF-IR cells progressively increased in number with age, and then decreased in adults; (group 3) numerous BDNF-IR cells detected between PND 1 and 7 showed a dramatic reductions in number with few IR cells in adults. In contrast, the developmental pattern of most BDNF-IR fibers differed from that of IR neurons, i.e. they appeared between PND 1-28 and thereafter continued to increase in number showing a maximum level in adults. Additionally, BDNF-IR cells in the superficial layer of the neocortex and IR fibers in the stratum oriens of CA2 first appeared as late as PND 28 and in adults, respectively. After colchicine treatment, reexpression or a marked increase in the number of BDNF-IR neurons was observed in many areas of the adult brain where a progressive decrease in BDNF-IR cell numbers during development and scant or some IR neurons in adults were shown. These results showed both transient and persistent expression of BDNF in various regions of the developing rat brain.

  19. Differential regulation of laminin b1 transgene expression in the neonatal and adult mouse brain.

    PubMed

    Sharif, K A; Baker, H; Gudas, L J

    2004-01-01

    Laminins are the major glycoproteins present in basement membrane, a type of extracellular matrix. We showed that the LAMB1 gene, which encodes the laminin beta1 subunit, is transcriptionally activated by retinoic acid in embryonic stem cells. However, little information is available concerning LAMB1 developmental regulation and spatial expression in the adult mouse brain. In this study we used transgenic mice expressing different lengths of LAMB1 promoter driving beta-galactosidase to investigate developmental and adult transcriptional regulation in the regions of the brain in which the laminin beta1 protein is expressed. CNS expression was not observed in transgenic mice carrying a 1.4LAMB1betagal construct. Mice carrying a 2.5LAMB1betagal construct expressed the LAMB1 transgene, as assayed by X-gal staining, only in the molecular layer of the neonatal cerebellum. In contrast, a 3.9LAMB1betagal transgene showed broad regional expression in the adult mouse brain, including the hippocampus, entorhinal cortex, colliculi, striatum, and substantia nigra. Similar expression patterns were observed for the endogenous laminin beta1 protein and for the 3.9LAMB1betagal transgene, analyzed with an antibody against the beta-galactosidase protein. The 3.9LAMB1betagal transgene expression in the hippocampal tri-synaptic circuit suggests a role for the LAMB1 gene in learning and memory.

  20. Pedophilic brain potential responses to adult erotic stimuli.

    PubMed

    Knott, Verner; Impey, Danielle; Fisher, Derek; Delpero, Emily; Fedoroff, Paul

    2016-02-01

    Cognitive mechanisms associated with the relative lack of sexual interest in adults by pedophiles are poorly understood and may benefit from investigations examining how the brain processes adult erotic stimuli. The current study used event-related brain potentials (ERP) to investigate the time course of the explicit processing of erotic, emotional, and neutral pictures in 22 pedophilic patients and 22 healthy controls. Consistent with previous studies, early latency anterior ERP components were highly selective for erotic pictures. Although the ERPs elicited by emotional stimuli were similar in patients and controls, an early frontal positive (P2) component starting as early as 185 ms was significantly attenuated and slow to onset in pedophilia, and correlated with a clinical measure of cognitive distortions. Failure of rapid attentional capture by erotic stimuli suggests a relative reduction in early processing in pedophilic patients which may be associated with relatively diminished sexual interest in adults.

  1. Experience-dependent neural plasticity in the adult damaged brain

    PubMed Central

    Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

    2011-01-01

    Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper extremity (hand and arm) impairments. A prolonged and widespread process of repair and reorganization of surviving neural circuits is instigated by injury to the adult brain. When experience impacts these same neural circuits, it interacts with degenerative and regenerative cascades to shape neural reorganization and functional outcome. This is evident in the cortical plasticity resulting from compensatory reliance on the “good” forelimb in rats with unilateral sensorimotor cortical infarcts. Behavioral interventions (e.g., rehabilitative training) can drive functionally beneficial neural reorganization in the injured hemisphere. However, experience can have both behaviorally beneficial and detrimental effects. The interactions between experience-dependent and injury-induced neural plasticity are complex, time-dependent, and varied with age and other factors. A better understanding of these interactions is needed to understand how to optimize brain remodeling and functional outcome. Learning outcomes Readers will be able to describe (a) experience effects that are maladaptive for behavioral outcome after brain damage, (b) manipulations of experience that drive functionally beneficial neural plasticity, and (c) reasons why rehabilitative training effects can be expected to vary with age, training duration and timing. PMID:21620413

  2. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    PubMed

    Zhang, Kuan; Zhou, Yanzhao; Zhao, Tong; Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  3. In vivo sensitivity of the embryonic and adult neural stem cell compartments to low-dose radiation

    PubMed Central

    Barazzuol, Lara; Jeggo, Penny A.

    2016-01-01

    The embryonic brain is radiation-sensitive, with cognitive deficits being observed after exposure to low radiation doses. Exposure of neonates to radiation can cause intracranial carcinogenesis. To gain insight into the basis underlying these outcomes, we examined the response of the embryonic, neonatal and adult brain to low-dose radiation, focusing on the neural stem cell compartments. This review summarizes our recent findings. At E13.5–14.5 the embryonic neocortex encompasses rapidly proliferating stem and progenitor cells. Exploiting mice with a hypomorphic mutation in DNA ligase IV (Lig4Y288C), we found a high level of DNA double-strand breaks (DSBs) at E14.5, which we attribute to the rapid proliferation. We observed endogenous apoptosis in Lig4Y288C embryos and in WT embryos following exposure to low radiation doses. An examination of DSB levels and apoptosis in adult neural stem cell compartments, the subventricular zone (SVZ) and the subgranular zone (SGZ) revealed low DSB levels in Lig4Y288C mice, comparable with the levels in differentiated neuronal tissues. We conclude that the adult SVZ does not incur high levels of DNA breakage, but sensitively activates apoptosis; apoptosis was less sensitively activated in the SGZ, and differentiated neuronal tissues did not activate apoptosis. P5/P15 mice showed intermediate DSB levels, suggesting that DSBs generated in the embryo can be transmitted to neonates and undergo slow repair. Interestingly, this analysis revealed a stage of high endogenous apoptosis in the neonatal SVZ. Collectively, these studies reveal that the adult neural stem cell compartment, like the embryonic counterpart, can sensitively activate apoptosis. PMID:27125639

  4. PET imaging of neurogenic activity in the adult brain: Toward in vivo imaging of human neurogenesis.

    PubMed

    Tamura, Yasuhisa; Kataoka, Yosky

    2017-01-01

    Neural stem cells are present in 2 neurogenic regions, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), and continue to generate new neurons throughout life. Adult hippocampal neurogenesis is linked to a variety of psychiatric disorders such as depression and anxiety, and to the therapeutic effects of antidepressants, as well as learning and memory. In vivo imaging for hippocampal neurogenic activity may be used to diagnose psychiatric disorders and evaluate the therapeutic efficacy of antidepressants. However, these imaging techniques remain to be established until now. Recently, we established a quantitative positron emission tomography (PET) imaging technique for neurogenic activity in the adult brain with 3'-deoxy-3'-[(18)F]fluoro-L-thymidine ([(18)F]FLT) and probenecid, a drug transporter inhibitor in blood-brain barrier. Moreover, we showed that this PET imaging technique can monitor alterations in neurogenic activity in the hippocampus of adult rats with depression and following treatment with an antidepressant. This PET imaging method may assist in diagnosing depression and in monitoring the therapeutic efficacy of antidepressants. In this commentary, we discuss the possibility of in vivo PET imaging for neurogenic activity in adult non-human primates and humans.

  5. Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration.

    PubMed

    Reimer, Michell M; Norris, Anneliese; Ohnmacht, Jochen; Patani, Rickie; Zhong, Zhen; Dias, Tatyana B; Kuscha, Veronika; Scott, Angela L; Chen, Yu-Chia; Rozov, Stanislav; Frazer, Sarah L; Wyatt, Cameron; Higashijima, Shin-ichi; Patton, E Elizabeth; Panula, Pertti; Chandran, Siddharthan; Becker, Thomas; Becker, Catherina G

    2013-06-10

    Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

  6. Relationships between gene expression and brain wiring in the adult rodent brain.

    PubMed

    French, Leon; Pavlidis, Paul

    2011-01-06

    We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain "connectome" from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.

  7. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

    PubMed Central

    Bell, Robert D.; Winkler, Ethan A.; Sagare, Abhay P.; Singh, Itender; LaRue, Barb; Deane, Rashid; Zlokovic, Berislav V.

    2010-01-01

    SUMMARY Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow and cerebral blood flow responses to brain activation which ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericytes loss results in a progressive age-dependent vascular-mediated neurodegeneration. PMID:21040844

  8. Biomaterial microenvironments to support the generation of new neurons in the adult brain.

    PubMed

    Conway, Anthony; Schaffer, David V

    2014-05-01

    Neural stem cells (NSC) in two regions of the adult mammalian brain--the subventricular zone (SVZ) and hippocampus--continuously generate new neurons, enabled by a complex repertoire of factors that precisely regulate the activation, proliferation, differentiation, and integration of the newborn cells. A growing number of studies also report low-level neurogenesis in regions of the adult brain outside these established neurogenic niches--potentially via NSC recruitment or activation of local, quiescent NSCs--under perturbations such as ischemia, cell death, or viral gene delivery of proneural growth factors. We have explored whether implantation of engineered biomaterials can stimulate neurogenesis in normally quiescent regions of the brain. Specifically, recombinant versions of factors found within the NSC microenvironment, Sonic hedgehog, and ephrin-B2 were conjugated to long polymers, thereby creating highly bioactive, multivalent ligands that begin to emulate components of the neurogenic niche. In this engineered biomaterial microenvironment, new neuron formation was observed in normally non-neurogenic regions of the brain, the striatum, and the cortex, and combining these multivalent biomaterials with stromal cell-derived factor-1α increased neuronal commitment of newly divided cells seven- to eightfold in these regions. Additionally, the decreased hippocampal neurogenesis of geriatric rodents was partially rescued toward levels of young animals. We thus demonstrate for the first time de novo neurogenesis in both the cortex and striatum of adult rodents stimulated solely by delivery of synthetic biomaterial forms of proteins naturally found within adult neurogenic niches, offering the potential to replace neurons lost in neurodegenerative disease or injury as an alternative to cell implantation.

  9. Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes.

    PubMed

    Li, Xiaoheng; Wang, Zhao; Jiang, Zhenming; Guo, Jingjing; Zhang, Yuxi; Li, Chenhao; Chung, Jinyong; Folmer, Janet; Liu, June; Lian, Qingquan; Ge, Renshan; Zirkin, Barry R; Chen, Haolin

    2016-03-08

    Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor β (TGF-β). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-β, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry.

  10. Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human induced pluripotent stem cells.

    PubMed

    Srikanth, Priya; Young-Pearse, Tracy L

    2014-01-01

    Seven years have passed since the initial report of the generation of induced pluripotent stem cells (iPSCs) from adult human somatic cells, and in the intervening time the field of neuroscience has developed numerous disease models using this technology. Here, we review progress in the field and describe both the advantages and potential pitfalls of modeling neurodegenerative and neurodevelopmental diseases using this technology. We include tables with information on neural differentiation protocols and studies that developed human iPSC lines to model neurological diseases. We also discuss how one can: investigate effects of genetic mutations with iPSCs, examine cell fate-specific phenotypes, best determine the specificity of a phenotype, and bring in vivo relevance to this in vitro technique.

  11. Life Satisfaction in Adult Survivors of Childhood Brain Tumors

    PubMed Central

    Crom, Deborah B.; Li, Zhenghong; Brinkman, Tara M.; Hudson, Melissa M.; Armstrong, Gregory T.; Neglia, Joseph; Ness, Kirsten K.

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, life-long deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors’ physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggests some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population–based matched controls. Chi-square tests, t-tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors’ general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population. PMID:25027187

  12. Life satisfaction in adult survivors of childhood brain tumors.

    PubMed

    Crom, Deborah B; Li, Zhenghong; Brinkman, Tara M; Hudson, Melissa M; Armstrong, Gregory T; Neglia, Joseph; Ness, Kirsten K

    2014-01-01

    Adult survivors of childhood brain tumors experience multiple, significant, lifelong deficits as a consequence of their malignancy and therapy. Current survivorship literature documents the substantial impact such impairments have on survivors' physical health and quality of life. Psychosocial reports detail educational, cognitive, and emotional limitations characterizing survivors as especially fragile, often incompetent, and unreliable in evaluating their circumstances. Anecdotal data suggest some survivors report life experiences similar to those of healthy controls. The aim of our investigation was to determine whether life satisfaction in adult survivors of childhood brain tumors differs from that of healthy controls and to identify potential predictors of life satisfaction in survivors. This cross-sectional study compared 78 brain tumor survivors with population-based matched controls. Chi-square tests, t tests, and linear regression models were used to investigate patterns of life satisfaction and identify potential correlates. Results indicated that life satisfaction of adult survivors of childhood brain tumors was similar to that of healthy controls. Survivors' general health expectations emerged as the primary correlate of life satisfaction. Understanding life satisfaction as an important variable will optimize the design of strategies to enhance participation in follow-up care, reduce suffering, and optimize quality of life in this vulnerable population.

  13. Multipotent (adult) and pluripotent stem cells for heart regeneration: what are the pros and cons?

    PubMed

    Liao, Song-Yan; Tse, Hung-Fat

    2013-12-24

    Heart failure after myocardial infarction is the leading cause of mortality and morbidity worldwide. Existing medical and interventional therapies can only reduce the loss of cardiomyocytes during myocardial infarction but are unable to replenish the permanent loss of cardiomyocytes after the insult, which contributes to progressive pathological left ventricular remodeling and progressive heart failure. As a result, cell-based therapies using multipotent (adult) stem cells and pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) have been explored as potential therapeutic approaches to restore cardiac function in heart failure. Nevertheless, the optimal cell type with the best therapeutic efficacy and safety for heart regeneration is still unknown. In this review, the potential pros and cons of different types of multipotent (adult) stem cells and pluripotent stem cells that have been investigated in preclinical and clinical studies are reviewed, and the future perspective of stem cell-based therapy for heart regeneration is discussed.

  14. 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.

  15. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier.

    PubMed

    Burgess, Alison; Ayala-Grosso, Carlos A; Ganguly, Milan; Jordão, Jessica F; Aubert, Isabelle; Hynynen, Kullervo

    2011-01-01

    Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation.

  16. 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).

  17. Sox10(+) adult stem cells contribute to biomaterial encapsulation and microvascularization.

    PubMed

    Wang, Dong; Wang, Aijun; Wu, Fan; Qiu, Xuefeng; Li, Ye; Chu, Julia; Huang, Wen-Chin; Xu, Kang; Gong, Xiaohua; Li, Song

    2017-01-10

    Implanted biomaterials and biomedical devices generally induce foreign body reaction and end up with encapsulation by a dense avascular fibrous layer enriched in extracellular matrix. Fibroblasts/myofibroblasts are thought to be the major cell type involved in encapsulation, but it is unclear whether and how stem cells contribute to this process. Here we show, for the first time, that Sox10(+) adult stem cells contribute to both encapsulation and microvessel formation. Sox10(+) adult stem cells were found sparsely in the stroma of subcutaneous loose connective tissues. Upon subcutaneous biomaterial implantation, Sox10(+) stem cells were activated and recruited to the biomaterial scaffold, and differentiated into fibroblasts and then myofibroblasts. This differentiation process from Sox10(+) stem cells to myofibroblasts could be recapitulated in vitro. On the other hand, Sox10(+) stem cells could differentiate into perivascular cells to stabilize newly formed microvessels. Sox10(+) stem cells and endothelial cells in three-dimensional co-culture self-assembled into microvessels, and platelet-derived growth factor had chemotactic effect on Sox10(+) stem cells. Transplanted Sox10(+) stem cells differentiated into smooth muscle cells to stabilize functional microvessels. These findings demonstrate the critical role of adult stem cells in tissue remodeling and unravel the complexity of stem cell fate determination.

  18. Sox10+ adult stem cells contribute to biomaterial encapsulation and microvascularization

    PubMed Central

    Wang, Dong; Wang, Aijun; Wu, Fan; Qiu, Xuefeng; Li, Ye; Chu, Julia; Huang, Wen-Chin; Xu, Kang; Gong, Xiaohua; Li, Song

    2017-01-01

    Implanted biomaterials and biomedical devices generally induce foreign body reaction and end up with encapsulation by a dense avascular fibrous layer enriched in extracellular matrix. Fibroblasts/myofibroblasts are thought to be the major cell type involved in encapsulation, but it is unclear whether and how stem cells contribute to this process. Here we show, for the first time, that Sox10+ adult stem cells contribute to both encapsulation and microvessel formation. Sox10+ adult stem cells were found sparsely in the stroma of subcutaneous loose connective tissues. Upon subcutaneous biomaterial implantation, Sox10+ stem cells were activated and recruited to the biomaterial scaffold, and differentiated into fibroblasts and then myofibroblasts. This differentiation process from Sox10+ stem cells to myofibroblasts could be recapitulated in vitro. On the other hand, Sox10+ stem cells could differentiate into perivascular cells to stabilize newly formed microvessels. Sox10+ stem cells and endothelial cells in three-dimensional co-culture self-assembled into microvessels, and platelet-derived growth factor had chemotactic effect on Sox10+ stem cells. Transplanted Sox10+ stem cells differentiated into smooth muscle cells to stabilize functional microvessels. These findings demonstrate the critical role of adult stem cells in tissue remodeling and unravel the complexity of stem cell fate determination. PMID:28071739

  19. Behavior of neural stem cells in the Alzheimer brain

    PubMed Central

    Waldau, B.; Shetty, A. K.

    2013-01-01

    Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid peptides (Aβ) and a progressive loss of neurons leading to dementia. Because hippocampal neurogenesis is linked to functions such as learning, memory and mood, there has been great interest in examining the effects of AD on hippocampal neurogenesis. This article reviews the pertinent studies and tries to unite them in one possible disease model. Early in the disease, oligomeric Aβ may transiently promote the generation of immature neurons from neural stem cells (NSCs). However, reduced concentrations of multiple neurotrophic factors and higher levels of fibroblast growth factor-2 seem to induce a developmental arrest of newly generated neurons. Furthermore, fibrillary Aβ and down-regulation of oligodendrocyte-lineage transcription factor-2 (OLIG2) may cause the death of these nonfunctional neurons. Therefore, altering the brain microenvironment for fostering apt maturation of graft-derived neurons may be critical for improving the efficacy of NSC transplantation therapy for AD. PMID:18500448

  20. Decreased segregation of brain systems across the healthy adult lifespan

    PubMed Central

    Chan, Micaela Y.; Park, Denise C.; Savalia, Neil K.; Petersen, Steven E.; Wig, Gagan S.

    2014-01-01

    Healthy aging has been associated with decreased specialization in brain function. This characterization has focused largely on describing age-accompanied differences in specialization at the level of neurons and brain areas. We expand this work to describe systems-level differences in specialization in a healthy adult lifespan sample (n = 210; 20–89 y). A graph-theoretic framework is used to guide analysis of functional MRI resting-state data and describe systems-level differences in connectivity of individual brain networks. Young adults’ brain systems exhibit a balance of within- and between-system correlations that is characteristic of segregated and specialized organization. Increasing age is accompanied by decreasing segregation of brain systems. Compared with systems involved in the processing of sensory input and motor output, systems mediating “associative” operations exhibit a distinct pattern of reductions in segregation across the adult lifespan. Of particular importance, the magnitude of association system segregation is predictive of long-term memory function, independent of an individual’s age. PMID:25368199

  1. Prenatal ethanol exposure increases brain cholesterol content in adult rats.

    PubMed

    Barceló-Coblijn, Gwendolyn; Wold, Loren E; Ren, Jun; Murphy, Eric J

    2013-11-01

    Fetal alcohol syndrome is the most severe expression of the fetal alcohol spectrum disorders (FASD). Although alterations in fetal and neonate brain fatty acid composition and cholesterol content are known to occur in animal models of FASD, the persistence of these alterations into adulthood is unknown. To address this question, we determined the effect of prenatal ethanol exposure on individual phospholipid class fatty acid composition, individual phospholipid class mass, and cholesterol mass in brains from 25-week-old rats that were exposed to ethanol during gestation beginning at gestational day 2. While total phospholipid mass was unaffected, phosphatidylinositol and cardiolipin mass was decreased 14 and 43 %, respectively. Exposure to prenatal ethanol modestly altered brain phospholipid fatty acid composition, and the most consistent change was a significant 1.1-fold increase in total polyunsaturated fatty acids (PUFA), in the n-3/n-6 ratio, and in the 22:6n-3 content in ethanolamine glycerophospholipids and in phosphatidylserine. In contrast, prenatal ethanol consumption significantly increased brain cholesterol mass 1.4-fold and the phospholipid to cholesterol ratio was significantly increased 1.3-fold. These results indicate that brain cholesterol mass was significantly increased in adult rats exposed prenatally to ethanol, but changes in phospholipid mass and phospholipid fatty acid composition were extremely limited. Importantly, suppression of postnatal ethanol consumption was not sufficient to reverse the large increase in cholesterol observed in the adult rats.

  2. Brain-stem Listeriosis: A Comparison of SPECT and MRI Findings

    PubMed Central

    Sahin, Sevki; Arisoy, Ayse S.; Topkaya, Aynur E.; Karsidag, Sibel

    2006-01-01

    Abstract and Introduction Abstract Listeria monocytogenes, although uncommon as a cause of illness in the general population, can result in serious illness when it affects pregnant women, neonates, the elderly, and immunocompromised individuals. Typically, it is a food-borne organism. This report describes a case of brain-stem listeriosis in a previously healthy 51-year-old woman. The diagnosis was based on clinical findings, the results of cerebrospinal fluid (CSF) analysis, CSF culture, and magnetic resonance imaging (MRI) findings. MRI demonstrated upper brain stem and cerebellar peduncle involvement. In addition, Tc-99m exametazime (HMPAO)-labeled single photon emission computed tomography (SPECT) of the brain revealed bilateral cerebellar hypoperfusion. Antibiotic therapy resulted in partial clinical recovery after 3 weeks. At the end of 6 months, brain-stem findings had nearly resolved. However, although minimal residual findings were observed on MRI at 6 months, bilateral diffuse cerebellar hypoperfusion remained on Tc-99m HMPAO brain SPECT. PMID:17415328

  3. Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

    PubMed

    Cox, Charles S; Hetz, Robert A; Liao, George P; Aertker, Benjamin M; Ewing-Cobbs, Linda; Juranek, Jenifer; Savitz, Sean I; Jackson, Margaret L; Romanowska-Pawliczek, Anna M; Triolo, Fabio; Dash, Pramod K; Pedroza, Claudia; Lee, Dean A; Worth, Laura; Aisiku, Imoigele P; Choi, Huimahn A; Holcomb, John B; Kitagawa, Ryan S

    2017-04-01

    that correlated with functional outcomes. Key inflammatory cytokines were downregulated. Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Stem Cells 2016 Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065-1079.

  4. Clinical review: Brain-body temperature differences in adults with severe traumatic brain injury.

    PubMed

    Childs, Charmaine; Lunn, Kueh Wern

    2013-04-22

    Surrogate or 'proxy' measures of brain temperature are used in the routine management of patients with brain damage. The prevailing view is that the brain is 'hotter' than the body. The polarity and magnitude of temperature differences between brain and body, however, remains unclear after severe traumatic brain injury (TBI). The focus of this systematic review is on the adult patient admitted to intensive/neurocritical care with a diagnosis of severe TBI (Glasgow Coma Scale score of less than 8). The review considered studies that measured brain temperature and core body temperature. Articles published in English from the years 1980 to 2012 were searched in databases, CINAHL, PubMed, Scopus, Web of Science, Science Direct, Ovid SP, Mednar and ProQuest Dissertations & Theses Database. For the review, publications of randomised controlled trials, non-randomised controlled trials, before and after studies, cohort studies, case-control studies and descriptive studies were considered for inclusion. Of 2,391 records identified via the search strategies, 37 were retrieved for detailed examination (including two via hand searching). Fifteen were reviewed and assessed for methodological quality. Eleven studies were included in the systematic review providing 15 brain-core body temperature comparisons. The direction of mean brain-body temperature differences was positive (brain higher than body temperature) and negative (brain lower than body temperature). Hypothermia is associated with large brain-body temperature differences. Brain temperature cannot be predicted reliably from core body temperature. Concurrent monitoring of brain and body temperature is recommended in patients where risk of temperature-related neuronal damage is a cause for clinical concern and when deliberate induction of below-normal body temperature is instituted.

  5. Electrophysiological Recording in the Brain of Intact Adult Zebrafish

    PubMed Central

    Johnston, Lindsey; Ball, Rebecca E.; Acuff, Seth; Gaudet, John; Sornborger, Andrew; Lauderdale, James D.

    2013-01-01

    Previously, electrophysiological studies in adult zebrafish have been limited to slice preparations or to eye cup preparations and electrorentinogram recordings. This paper describes how an adult zebrafish can be immobilized, intubated, and used for in vivo electrophysiological experiments, allowing recording of neural activity. Immobilization of the adult requires a mechanism to deliver dissolved oxygen to the gills in lieu of buccal and opercular movement. With our technique, animals are immobilized and perfused with habitat water to fulfill this requirement. A craniotomy is performed under tricaine methanesulfonate (MS-222; tricaine) anesthesia to provide access to the brain. The primary electrode is then positioned within the craniotomy window to record extracellular brain activity. Through the use of a multitube perfusion system, a variety of pharmacological compounds can be administered to the adult fish and any alterations in the neural activity can be observed. The methodology not only allows for observations to be made regarding changes in neurological activity, but it also allows for comparisons to be made between larval and adult zebrafish. This gives researchers the ability to identify the alterations in neurological activity due to the introduction of various compounds at different life stages. PMID:24300281

  6. Adult stem cel diferentiation and trafficking and their implications in disease.

    PubMed

    Zhuge, Ying; Liu, Zhao-Jun; Velazquez, Omaida C

    2010-01-01

    Stem cells are unspecialized precursor cells that mainly reside in the bone marrow and have important roles in the establishment of embryonic tissue. They also have critical functions during adulthood, where they replenish short-lived mature effector cells and regeneration of injured tissue. They have three main characteristics: self-renewal, differentiation and homeostatic control. In order to maintain a pool of stem cells that support the production of blood cells, stromal elements and connective tissue, stem cells must be able to constantly replenish their own number. They must also possess the ability to differentiate and give rise to a heterogeneous group of functional cells. Finally, stem cells must possess the ability to modulate and balance differentiation and self-renewal according to environmental stimuli and whole-organ needs to prevent the production of excessive number of effector cells.(1) In addition to formation of these cells, regulated movement of stem cells is critical for organogenesis, homeostasis and repair in adulthood. Stem cells require specific inputs from particular environments in order to perform their various functions. Some similar trafficking mechanisms are shared by leukocytes, adult and fetal stem cells, as well as cancer stem cells.(1,2) Achieving proper trafficking of stem cells will allow increased efficiency of targeted cell therapy and drug delivery.(2) In addition, understanding similarities and differences in homing and migration of malignant cancer stem cells will also clarify molecular events of tumor progression and metastasis.(2) This chapter focuses on the differentiation, trafficking and homing of the major types of adult bone marrow stem cells: hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) and the term"stem cell" will refer to "adult stem cells" unless otherwise specified.

  7. Cerebellar stem cells do not produce neurons and astrocytes in adult mouse

    SciTech Connect

    Su, Xin; Guan, Wuqiang; Yu, Yong-Chun; Fu, Yinghui

    2014-07-18

    Highlights: • No new neurons and astrocytes are generated in adult mouse cerebellum. • Very few mash1{sup +} or nestin{sup +} stem cells exist, and most of them are quiescent. • Cell proliferation rate is diversified among cerebellar regions and decreases over time. - Abstract: Although previous studies implied that cerebellar stem cells exist in some adult mammals, little is known about whether these stem cells can produce new neurons and astrocytes. In this study by bromodeoxyuridine (BrdU) intraperitoneal (i.p.) injection, we found that there are abundant BrdU{sup +} cells in adult mouse cerebellum, and their quantity and density decreases significantly over time. We also found cell proliferation rate is diversified in different cerebellar regions. Among these BrdU{sup +} cells, very few are mash1{sup +} or nestin{sup +} stem cells, and the vast majority of cerebellar stem cells are quiescent. Data obtained by in vivo retrovirus injection indicate that stem cells do not produce neurons and astrocytes in adult mouse cerebellum. Instead, some cells labeled by retrovirus are Iba1{sup +} microglia. These results indicate that very few stem cells exist in adult mouse cerebellum, and none of these stem cells contribute to neurogenesis and astrogenesis under physiological condition.

  8. The role of CD44 in fetal and adult hematopoietic stem cell regulation.

    PubMed

    Cao, Huimin; Heazlewood, Shen Y; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44(-/-) mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells.

  9. The role of CD44 in fetal and adult hematopoietic stem cell regulation

    PubMed Central

    Cao, Huimin; Heazlewood, Shen Y.; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K.

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44−/− mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells. PMID:26546504

  10. A meal preparation treatment protocol for adults with brain injury.

    PubMed

    Neistadt, M E

    1994-05-01

    Adults with acquired brain injury often demonstrate dysfunction in meal preparation due to deficits in component cognitive-perceptual skills. Although occupational therapy for these clients routinely includes meal preparation training, there are no protocols in the occupational therapy literature to help structure that activity to address clients' cognitive-perceptual deficits. This paper describes a meal preparation treatment protocol based on cognitive-perceptual information processing theory that has been pilot tested in a treatment outcome study with adult men with traumatic or anoxic acquired brain injury. In that study, the group of 23 subjects treated with this meal preparation protocol showed significant improvement in their meal preparation skill, as measured by the Rabideau Kitchen Evaluation-Revised (RKE-R), a test of meal preparation skill, and in their cognitive-perceptual skill, as measured by the WAIS-R Block Design Test. The treatment protocol includes descriptions of the structure, grading, and cuing methods for light meal preparation activities.

  11. Comprehensive cellular‐resolution atlas of the adult human brain

    PubMed Central

    Royall, Joshua J.; Sunkin, Susan M.; Ng, Lydia; Facer, Benjamin A.C.; Lesnar, Phil; Guillozet‐Bongaarts, Angie; McMurray, Bergen; Szafer, Aaron; Dolbeare, Tim A.; Stevens, Allison; Tirrell, Lee; Benner, Thomas; Caldejon, Shiella; Dalley, Rachel A.; Dee, Nick; Lau, Christopher; Nyhus, Julie; Reding, Melissa; Riley, Zackery L.; Sandman, David; Shen, Elaine; van der Kouwe, Andre; Varjabedian, Ani; Write, Michelle; Zollei, Lilla; Dang, Chinh; Knowles, James A.; Koch, Christof; Phillips, John W.; Sestan, Nenad; Wohnoutka, Paul; Zielke, H. Ronald; Hohmann, John G.; Jones, Allan R.; Bernard, Amy; Hawrylycz, Michael J.; Hof, Patrick R.; Fischl, Bruce

    2016-01-01

    ABSTRACT Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole‐brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high‐resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion‐weighted imaging (DWI), and 1,356 large‐format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto‐ and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127–3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:27418273

  12. Neural stem cells secrete factors facilitating brain regeneration upon constitutive Raf-Erk activation

    PubMed Central

    Rhee, Yong-Hee; Yi, Sang-Hoon; Kim, Joo Yeon; Chang, Mi-Yoon; Jo, A-Young; Kim, Jinyoung; Park, Chang-Hwan; Cho, Je-Yoel; Choi, Young-Jin; Sun, Woong; Lee, Sang-Hun

    2016-01-01

    The intracellular Raf-Erk signaling pathway is activated during neural stem cell (NSC) proliferation, and neuronal and astrocytic differentiation. A key question is how this signal can evoke multiple and even opposing NSC behaviors. We show here, using a constitutively active Raf (ca-Raf), that Raf-Erk activation in NSCs induces neuronal differentiation in a cell-autonomous manner. By contrast, it causes NSC proliferation and the formation of astrocytes in an extrinsic autocrine/paracrine manner. Thus, treatment of NSCs with medium (CM) conditioned in ca-Raf-transduced NSCs (Raf-CM; RCM) became activated to form proliferating astrocytes resembling radial glial cells (RGCs) or adult-type NSCs. Infusion of Raf-CM into injured mouse brains caused expansion of the NSC population in the subventricular zone, followed by the formation of new neurons that migrated to the damaged site. Our study shows an example how molecular mechanisms dissecting NSC behaviors can be utilized to develop regenerative therapies in brain disorders. PMID:27554447

  13. Adult neural stem cells from the subventricular zone: a review of the neurosphere assay.

    PubMed

    Gil-Perotín, Sara; Duran-Moreno, María; Cebrián-Silla, Arantxa; Ramírez, Mónica; García-Belda, Paula; García-Verdugo, José Manuel

    2013-09-01

    The possibility of obtaining large numbers of cells with potential to become functional neurons implies a great advance in regenerative medicine. A source of cells for therapy is the subventricular zone (SVZ) where adult neural stem cells (NSCs) retain the ability to proliferate, self-renew, and differentiate into several mature cell types. The neurosphere assay, a method to isolate, maintain, and expand these cells has been extensively utilized by research groups to analyze the biological properties of aNSCs and to graft into injured brains from animal models. In this review we briefly describe the neurosphere assay and its limitations, the methods to optimize culture conditions, the identity and the morphology of aNSC-derived neurospheres (including new ultrastructural data). The controversy regarding the identity and "stemness" of cells within the neurosphere is revised. The fine morphology of neurospheres, described thoroughly, allows for phenotypical characterization of cells in the neurospheres and may reveal slight changes that indirectly inform about cell integrity, cell damage, or oncogenic transformation. Along this review we largely highlight the critical points that researchers have to keep in mind before extrapolating results or translating experimental transplantation of neurosphere-derived cells to the clinical setting.

  14. Encapsulation of mesenchymal stem cells by bioscaffolds protects cell survival and attenuates neuroinflammatory reaction in injured brain tissue after transplantation.

    PubMed

    Sarnowska, Anna; Jablonska, Anna; Jurga, Marcin; Dainiak, Maria; Strojek, Lukasz; Drela, Katarzyna; Wright, Kathleen; Tripathi, Anuj; Kumar, Ashok; Jungvid, Hans; Lukomska, Barbara; Forraz, Nico; McGuckin, Colin; Domanska-Janik, Krystyna

    2013-01-01

    Since the brain is naturally inefficient in regenerating functional tissue after injury or disease, novel restorative strategies including stem cell transplantation and tissue engineering have to be considered. We have investigated the use of such strategies in order to achieve better functional repair outcomes. One of the fundamental challenges of successful transplantation is the delivery of cells to the injured site while maintaining cell viability. Classical cell delivery methods of intravenous or intraparenchymal injections are plagued by low engraftment and poor survival of transplanted stem cells. Novel implantable devices such as 3D bioactive scaffolds can provide the physical and metabolic support required for successful progenitor cell engraftment, proliferation, and maturation. In this study, we performed in situ analysis of laminin-linked dextran and gelatin macroporous scaffolds. We revealed the protective action of gelatin-laminin (GL) scaffolds seeded with mesenchymal stem cells derived from donated human Wharton's jelly (hUCMSCs) against neuroinflammatory reactions of injured mammalian brain tissue. These bioscaffolds have been implanted into (i) intact and (ii) ischemic rat hippocampal organotypic slices and into the striatum of (iii) normal and (iv) focally injured brains of adult Wistar rats. We found that transplantation of hUCMSCs encapsulated in GL scaffolds had a significant impact on the prevention of glial scar formation (low glial acidic fibrillary protein) and in the reduction of neuroinflammation (low interleukin-6 and the microglial markers ED1 and Iba1) in the recipient tissue. Moreover, implantation of hUCMSCs encapsulated within GL scaffolds induced matrix metalloproteinase-2 and -9 proteolytic activities in the surrounding brain tissue. This facilitated scaffold biodegradation while leaving the remaining grafted hUCMSCs untouched. In conclusion, transplanting GL scaffolds preseeded with hUCMSCs into mammalian brain tissue escaped

  15. Ketone-body utilization by homogenates of adult rat brain

    SciTech Connect

    Lopes-Cardozo, M.; Klein, W.

    1982-06-01

    The regulation of ketone-body metabolism and the quantitative importance of ketone bodies as lipid precursors in adult rat brain has been studied in vitro. Utilization of ketone bodies and of pyruvate by homogenates of adult rat brain was measured and the distribution of /sup 14/C from (3-/sup 14/C)ketone bodies among the metabolic products was analysed. The rate of ketone-body utilization was maximal in the presence of added Krebs-cycle intermediates and uncouplers of oxidative phosphorylation. The consumption of acetoacetate was faster than that of D-3-hydroxybutyrate, whereas, pyruvate produced twice as much acetyl-CoA as acetoacetate under optimal conditions. Millimolar concentrations of ATP in the presence of uncoupler lowered the consumption of ketone bodies but not of pyruvate. Indirect evidence is presented suggesting that ATP interferes specifically with the mitochondrial uptake of ketone bodies. Interconversion of ketone bodies and the accumulation of acid-soluble intermediates (mainly citrate and glutamate) accounted for the major part of ketone-body utilization, whereas only a small part was oxidized to CO/sub 2/. Ketone bodies were not incorporated into lipids or protein. We conclude that adult rat-brain homogenates use ketone bodies exclusively for oxidative purposes.

  16. Brain network activity in monolingual and bilingual older adults.

    PubMed

    Grady, Cheryl L; Luk, Gigi; Craik, Fergus I M; Bialystok, Ellen

    2015-01-01

    Bilingual older adults typically have better performance on tasks of executive control (EC) than do their monolingual peers, but differences in brain activity due to language experience are not well understood. Based on studies showing a relation between the dynamic range of brain network activity and performance on EC tasks, we hypothesized that life-long bilingual older adults would show increased functional connectivity relative to monolinguals in networks related to EC. We assessed intrinsic functional connectivity and modulation of activity in task vs. fixation periods in two brain networks that are active when EC is engaged, the frontoparietal control network (FPC) and the salience network (SLN). We also examined the default mode network (DMN), which influences behavior through reduced activity during tasks. We found stronger intrinsic functional connectivity in the FPC and DMN in bilinguals than in monolinguals. Although there were no group differences in the modulation of activity across tasks and fixation, bilinguals showed stronger correlations than monolinguals between intrinsic connectivity in the FPC and task-related increases of activity in prefrontal and parietal regions. This bilingual difference in network connectivity suggests that language experience begun in childhood and continued throughout adulthood influences brain networks in ways that may provide benefits in later life.

  17. Brain Network Activity in Monolingual and Bilingual Older Adults

    PubMed Central

    Grady, Cheryl L.; Luk, Gigi; Craik, Fergus I.M.; Bialystok, Ellen

    2016-01-01

    Bilingual older adults typically have better performance on tasks of executive control (EC) than do their monolingual peers, but differences in brain activity due to language experience are not well understood. Based on studies showing a relation between the dynamic range of brain network activity and performance on EC tasks, we hypothesized that life-long bilingual older adults would show increased functional connectivity relative to monolinguals in networks related to EC. We assessed intrinsic functional connectivity and modulation of activity in task vs. fixation periods in two brain networks that are active when EC is engaged, the frontoparietal control network (FPC) and the salience network (SLN). We also examined the default mode network (DMN), which influences behavior through reduced activity during tasks. We found stronger intrinsic functional connectivity in the FPC and DMN in bilinguals than in monolinguals. Although there were no group differences in the modulation of activity across tasks and fixation, bilinguals showed stronger correlations than monolinguals between intrinsic connectivity in the FPC and task-related increases of activity in prefrontal and parietal regions. This bilingual difference in network connectivity suggests that language experience begun in childhood and continued throughout adulthood influences brain networks in ways that may provide benefits in later life. PMID:25445783

  18. The Yin and Yang of chromatin dynamics in adult stem cell fate selection

    PubMed Central

    Adam, Rene C.; Fuchs, Elaine

    2015-01-01

    Adult organisms rely on tissue stem cells for maintenance and repair. During homeostasis, the concerted action of local niche signals and epigenetic regulators establish stable gene expression patterns to ensure that stem cells are not lost over time. However, stem cells also provide host tissues with a remarkable plasticity to respond to perturbations. How adult stem cells choose and acquire new fates is unknown, but the genome-wide mapping of epigenetic landscapes suggests a critical role for chromatin remodeling in these processes. Here, we explore the emerging role of chromatin modifiers and pioneer transcription factors in adult stem cell fate decisions and plasticity, which ensure that selective lineage choices are only made when environmentally cued. PMID:26689127

  19. Time Spent Caregiving and Help Received by Spouses and Adult Children of Brain-Impaired Adults.

    ERIC Educational Resources Information Center

    Enright, Robert B., Jr.

    1991-01-01

    Surveyed 233 family caregivers for brain-impaired adults. Spousal caregivers (both husbands and wives) devoted much time to caregiving. Most caregivers received little assistance from other family members and friends, but husbands received more than others. Employed spouses received more paid help than unemployed spouses; employment did not affect…

  20. 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.

  1. Regional and Stage-Specific Effects of Prospectively Purified Vascular Cells on the Adult V-SVZ Neural Stem Cell Lineage

    PubMed Central

    Crouch, Elizabeth E.; Liu, Chang; Silva-Vargas, Violeta

    2015-01-01

    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. PMID:25788671

  2. Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders.

    PubMed

    Nixon, Kimberly; Morris, Stephanie A; Liput, Daniel J; Kelso, Matthew L

    2010-02-01

    This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescents. Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood. In adolescents with alcohol use disorders (AUDs), the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered. This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently among the age groups. Finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an AUD.

  3. Expression of polysialylated neural cell adhesion molecules on adult stem cells after neuronal differentiation of inner ear spiral ganglion neurons

    SciTech Connect

    Park, Kyoung Ho; Yeo, Sang Won; Troy, Frederic A.

    2014-10-17

    Highlights: • PolySia expressed on neurons primarily during early stages of neuronal development. • PolySia–NCAM is expressed on neural stem cells from adult guinea pig spiral ganglion. • PolySia is a biomarker that modulates neuronal differentiation in inner ear stem cells. - Abstract: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia–NCAMs) modulate cell–cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia–NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb’s to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell–cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.

  4. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms.

    PubMed

    Prockop, Darwin J

    2009-06-01

    Research on stem cells has progressed at a rapid pace and, as might be anticipated, the results have generated several controversies, a few myths and a change in a major paradigm. Some of these issues will be reviewed in this study with special emphasis on how they can be applied to the adult stem/progenitor cells from bone marrow, referred to as MSCs.

  5. Epistatic adult plant resistance in wheat to stem rust cosegregates with Sr12 seedling resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wheat adult plant resistance (APR) to stem rust is desirable. Researchers have characterized the inheritance of APR in cultivar Thatcher as complex. In order to identify the loci providing APR in Thatcher, we evaluated 160 RILs derived from Thatcher/McNeal for stem rust reaction in the field in Keny...

  6. Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine.

    PubMed

    Chen, Ching-Huan; Luhur, Arthur; Sokol, Nicholas

    2015-10-15

    Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration.

  7. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    PubMed

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  8. Brain stem auditory evoked potentials: effects of ovarian steroids correlated with increased incidence of Bell's palsy in pregnancy.

    PubMed

    Ben David, Y; Tal, J; Podoshin, L; Fradis, M; Sharf, M; Pratt, H; Faraggi, D

    1995-07-01

    To investigate the effect of ovarian steroids on the brain stem during changes of estrogen and progesterone blood levels, we recorded brain stem auditory evoked potentials with increased stimulus rates from 26 women treated for sterility by menotropins (Pergonal and Metrodin). These women were divided into three groups according to their estrogen and progesterone blood levels. The brain stem auditory evoked potential results revealed a significant delay of peak III only, with an increased stimulus rate in the group with the highest estrogen level. Estrogen may cause a brain stem synaptic impairment, presumably because of ischemic changes, and thus also may be responsible for a higher incidence of Bell's palsy during pregnancy.

  9. Enhanced ex vivo expansion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM.

    PubMed

    Ng, Chee Ping; Sharif, Abdul Rahim Mohamed; Heath, Daniel E; Chow, John W; Zhang, Claire B Y; Chan-Park, Mary B; Hammond, Paula T; Chan, Jerry K Y; Griffith, Linda G

    2014-04-01

    Large-scale expansion of highly functional adult human mesenchymal stem cells (aMSCs) remains technologically challenging as aMSCs lose self renewal capacity and multipotency during traditional long-term culture and their quality/quantity declines with donor age and disease. Identification of culture conditions enabling prolonged expansion and rejuvenation would have dramatic impact in regenerative medicine. aMSC-derived decellularized extracellular matrix (ECM) has been shown to provide such microenvironment which promotes MSC self renewal and "stemness". Since previous studies have demonstrated superior proliferation and osteogenic potential of human fetal MSCs (fMSCs), we hypothesize that their ECM may promote expansion of clinically relevant aMSCs. We demonstrated that aMSCs were more proliferative (∼ 1.6 ×) on fMSC-derived ECM than aMSC-derived ECMs and traditional tissue culture wares (TCPS). These aMSCs were smaller and more uniform in size (median ± interquartile range: 15.5 ± 4.1 μm versus 17.2 ± 5.0 μm and 15.5 ± 4.1 μm for aMSC ECM and TCPS respectively), exhibited the necessary biomarker signatures, and stained positive for osteogenic, adipogenic and chondrogenic expressions; indications that they maintained multipotency during culture. Furthermore, fMSC ECM improved the proliferation (∼ 2.2 ×), size (19.6 ± 11.9 μm vs 30.2 ± 14.5 μm) and differentiation potential in late-passaged aMSCs compared to TCPS. In conclusion, we have established fMSC ECM as a promising cell culture platform for ex vivo expansion of aMSCs.

  10. Adult bone marrow-derived stem cells for organ regeneration and repair.

    PubMed

    Tögel, Florian; Westenfelder, Christof

    2007-12-01

    Stem cells have been recognized as a potential tool for the development of innovative therapeutic strategies. There are in general two types of stem cells, embryonic and adult stem cells. While embryonic stem cell therapy has been riddled with problems of allogeneic rejection and ethical concerns, adult stem cells have long been used in the treatment of hematological malignancies. With the recognition of additional, potentially therapeutic characteristics, bone marrow-derived stem cells have become a tool in regenerative medicine. The bone marrow is an ideal source of stem cells because it is easily accessible and harbors two types of stem cells. Hematopoietic stem cells give rise to all blood cell types and have been shown to exhibit plasticity, while multipotent marrow stromal cells are the source of osteocytes, chondrocytes, and fat cells and have been shown to support and generate a large number of different cell types. This review describes the general characteristics of these stem cell populations and their current and potential future applications in regenerative medicine.

  11. 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.

  12. Acute moderate exercise enhances compensatory brain activation in older adults.

    PubMed

    Hyodo, Kazuki; Dan, Ippeita; Suwabe, Kazuya; Kyutoku, Yasushi; Yamada, Yuhki; Akahori, Mitsuya; Byun, Kyeongho; Kato, Morimasa; Soya, Hideaki

    2012-11-01

    A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation.

  13. Mapping of brain lipid binding protein (Blbp) in the brain of adult zebrafish, co-expression with aromatase B and links with proliferation.

    PubMed

    Diotel, Nicolas; Vaillant, Colette; Kah, Olivier; Pellegrini, Elisabeth

    2016-01-01

    Adult fish exhibit a strong neurogenic capacity due to the persistence of radial glial cells. In zebrafish, radial glial cells display well-established markers such as the estrogen-synthesizing enzyme (AroB) and the brain lipid binding protein (Blbp), which is known to strongly bind omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). While Blpb is mainly described in the telencephalon of adult zebrafish, its expression in the remaining regions of the brain is poorly documented. The present study was designed to further investigate Blbp expression in the brain, its co-expression with AroB, and its link with radial glial cells proliferation in zebrafish. We generated a complete and detailed mapping of Blbp expression in the whole brain and show its complete co-expression with AroB, except in some tectal and hypothalamic regions. By performing PCNA and Blbp immunohistochemistry on cyp19a1b-GFP (AroB-GFP) fish, we also demonstrated preferential Blbp expression in proliferative radial glial cells in almost all regions studied. To our knowledge, this is the first complete and detailed mapping of Blbp-expressing cells showing strong association between Blbp and radial glial cell proliferation in the adult brain of fish. Given that zebrafish is now recognized models for studying neurogenesis and brain repair, our data provide detailed characterization of Blbp in the entire brain and open up a broad field of research investigating the role of omega-3 polyunsaturated fatty acids in neural stem cell activity in fish.

  14. Neuroimaging in adult penetrating brain injury: a guide for radiographers

    PubMed Central

    Temple, Nikki; Donald, Cortny; Skora, Amanda; Reed, Warren

    2015-01-01

    Penetrating brain injuries (PBI) are a medical emergency, often resulting in complex damage and high mortality rates. Neuroimaging is essential to evaluate the location and extent of injuries, and to manage them accordingly. Currently, a myriad of imaging modalities are included in the diagnostic workup for adult PBI, including skull radiography, computed tomography (CT), magnetic resonance imaging (MRI) and angiography, with each modality providing their own particular benefits. This literature review explores the current modalities available for investigating PBI and aims to assist in decision making for the appropriate use of diagnostic imaging when presented with an adult PBI. Based on the current literature, the authors have developed an imaging pathway for adult penetrating brain injury that functions as both a learning tool and reference guide for radiographers and other health professionals. Currently, CT is recommended as the imaging modality of choice for the initial assessment of PBI patients, while MRI is important in the sub-acute setting where it aids prognosis prediction and rehabilitation planning, Additional follow-up imaging, such as angiography, should be dependent upon clinical findings. PMID:26229677

  15. Neuroimaging in adult penetrating brain injury: a guide for radiographers.

    PubMed

    Temple, Nikki; Donald, Cortny; Skora, Amanda; Reed, Warren

    2015-06-01

    Penetrating brain injuries (PBI) are a medical emergency, often resulting in complex damage and high mortality rates. Neuroimaging is essential to evaluate the location and extent of injuries, and to manage them accordingly. Currently, a myriad of imaging modalities are included in the diagnostic workup for adult PBI, including skull radiography, computed tomography (CT), magnetic resonance imaging (MRI) and angiography, with each modality providing their own particular benefits. This literature review explores the current modalities available for investigating PBI and aims to assist in decision making for the appropriate use of diagnostic imaging when presented with an adult PBI. Based on the current literature, the authors have developed an imaging pathway for adult penetrating brain injury that functions as both a learning tool and reference guide for radiographers and other health professionals. Currently, CT is recommended as the imaging modality of choice for the initial assessment of PBI patients, while MRI is important in the sub-acute setting where it aids prognosis prediction and rehabilitation planning, Additional follow-up imaging, such as angiography, should be dependent upon clinical findings.

  16. Neuroimaging in adult penetrating brain injury: a guide for radiographers

    SciTech Connect

    Temple, Nikki; Donald, Cortny; Skora, Amanda; Reed, Warren

    2015-06-15

    Penetrating brain injuries (PBI) are a medical emergency, often resulting in complex damage and high mortality rates. Neuroimaging is essential to evaluate the location and extent of injuries, and to manage them accordingly. Currently, a myriad of imaging modalities are included in the diagnostic workup for adult PBI, including skull radiography, computed tomography (CT), magnetic resonance imaging (MRI) and angiography, with each modality providing their own particular benefits. This literature review explores the current modalities available for investigating PBI and aims to assist in decision making for the appropriate use of diagnostic imaging when presented with an adult PBI. Based on the current literature, the authors have developed an imaging pathway for adult penetrating brain injury that functions as both a learning tool and reference guide for radiographers and other health professionals. Currently, CT is recommended as the imaging modality of choice for the initial assessment of PBI patients, while MRI is important in the sub-acute setting where it aids prognosis prediction and rehabilitation planning, Additional follow-up imaging, such as angiography, should be dependent upon clinical findings.

  17. Isolation, cultivation, and characterization of adult murine prostate stem cells

    PubMed Central

    Lukacs, Rita U.; Goldstein, Andrew S.; Lawson, Devon A.; Cheng, Donghui; Witte, Owen N.

    2010-01-01

    ABSTRACT/SUMMARY The successful isolation and cultivation of prostate stem cells will allow us to study their unique biological properties and their application in therapeutic approaches. Here we provide step-by-step procedures on the basis of previous work in our laboratory for: the harvesting of primary prostate cells from adolescent male mice by a modified enzymatic procedure; the isolation of an enriched population of prostate stem cells through cell sorting; the cultivation of prostate stem cells in vitro; and characterization of these cells and their stem-like activity, including in vivo tubule regeneration. Normally it will take approximately 8 hours to harvest prostate cells, isolate the stem cell enriched population, and set up the in vitro sphere assay. It will take up to 8 weeks to analyze the unique properties of the stem cells, including their regenerative capacity in vivo. PMID:20360765

  18. Isolation, cultivation and characterization of adult murine prostate stem cells.

    PubMed

    Lukacs, Rita U; Goldstein, Andrew S; Lawson, Devon A; Cheng, Donghui; Witte, Owen N

    2010-04-01

    The successful isolation and cultivation of prostate stem cells will allow us to study their unique biological properties and their application in therapeutic approaches. Here we describe step-by-step procedures on the basis of previous work in our laboratory for the harvesting of primary prostate cells from adolescent male mice by a modified enzymatic procedure; the isolation of an enriched population of prostate stem cells through cell sorting; and the cultivation of prostate stem cells in vitro and characterization of these cells and their stem-like activity, including in vivo tubule regeneration. Normally, it will take approximately 8 h to harvest prostate cells, isolate the stem cell-enriched population and set up the in vitro sphere assay. It will take up to 8 weeks to analyze the unique properties of the stem cells, including their regenerative capacity in vivo.

  19. 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.

  20. Immune physiology and oogenesis in fetal and adult humans, ovarian infertility, and totipotency of adult ovarian stem cells.

    PubMed

    Bukovsky, Antonin; Caudle, Michael R; Virant-Klun, Irma; Gupta, Satish K; Dominguez, Roberto; Svetlikova, Marta; Xu, Fei

    2009-03-01

    It is still widely believed that while oocytes in invertebrates and lower vertebrates are periodically renewed throughout life, oocytes in humans and higher vertebrates are formed only during the fetal/perinatal period. However, this dogma is questioned, and clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal from ovarian stem cells (OSCs) in adult human ovaries, and of the role of third-party bone marrow-derived cells (monocyte-derived tissue macrophages and T lymphocytes) could help provide a better understanding of the causes of ovarian infertility, its prevention, and potential treatment. We have reported differentiation of distinct cell types from OSC and the production of new eggs in cultures derived from premenopausal and postmenopausal human ovaries. OSCs are also capable of producing neural/neuronal cells in vitro after sequential stimulation with sex steroid combinations. Hence, OSC represent a unique type of totipotent adult stem cells, which could be utilized for autologous treatment of premature ovarian failure and also for autologous stem cell therapy of neurodegenerative diseases without use of allogeneic embryonic stem cells or somatic cell nuclear transfer. The in vivo application of sex steroid combinations may augment the proliferation of existing neural stem cells and their differentiation into mature neuronal cells (systemic regenerative therapy). Such treatment may also stimulate the transdifferentiation of autologous neural stem cell precursors into neural stem cells useful for topical or systemic regenerative treatment.

  1. Somatic stem cells express Piwi and Vasa genes in an adult ctenophore: ancient association of "germline genes" with stemness.

    PubMed

    Alié, Alexandre; Leclère, Lucas; Jager, Muriel; Dayraud, Cyrielle; Chang, Patrick; Le Guyader, Hervé; Quéinnec, Eric; Manuel, Michaël

    2011-02-01

    Stem cells are essential for animal development and adult tissue homeostasis, and the quest for an ancestral gene fingerprint of stemness is a major challenge for evolutionary developmental biology. Recent studies have indicated that a series of genes, including the transposon silencer Piwi and the translational activator Vasa, specifically involved in germline determination and maintenance in classical bilaterian models (e.g., vertebrates, fly, nematode), are more generally expressed in adult multipotent stem cells in other animals like flatworms and hydras. Since the progeny of these multipotent stem cells includes both somatic and germinal derivatives, it remains unclear whether Vasa, Piwi, and associated genes like Bruno and PL10 were ancestrally linked to stemness, or to germinal potential. We have investigated the expression of Vasa, two Piwi paralogues, Bruno and PL10 in Pleurobrachia pileus, a member of the early-diverging phylum Ctenophora, the probable sister group of cnidarians. These genes were all expressed in the male and female germlines, and with the exception of one of the Piwi paralogues, they showed similar expression patterns within somatic territories (tentacle root, comb rows, aboral sensory complex). Cytological observations and EdU DNA-labelling and long-term retention experiments revealed concentrations of stem cells closely matching these gene expression areas. These stem cell pools are spatially restricted, and each specialised in the production of particular types of somatic cells. These data unveil important aspects of cell renewal within the ctenophore body and suggest that Piwi, Vasa, Bruno, and PL10 belong to a gene network ancestrally acting in two distinct contexts: (i) the germline and (ii) stem cells, whatever the nature of their progeny.

  2. RNA-Seq Reveals the Angiogenesis Diversity between the Fetal and Adults Bone Mesenchyme Stem Cell.

    PubMed

    Zhao, Xin; Han, Yingmin; Liang, Yu; Nie, Chao; Wang, Jian

    2016-01-01

    In this research, we used RNA sequencing (RNA-seq) to analyze 23 single cell samples and 2 bulk cells sample from human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. The results from the research demonstrated that there were big differences between two cell lines. Adult bone mesenchyme stem cell lines showed a strong trend on the blood vessel differentiation and cell motion, 48/49 vascular related differential expressed genes showed higher expression in adult bone mesenchyme stem cell lines (Abmsc) than fetal bone mesenchyme stem cell lines (Fbmsc). 96/106 cell motion related genes showed the same tendency. Further analysis showed that genes like ANGPT1, VEGFA, FGF2, PDGFB and PDGFRA showed higher expression in Abmsc. This work showed cell heterogeneity between human adult bone mesenchyme stem cell line and human fetal bone mesenchyme stem cell line. Also the work may give an indication that Abmsc had a better potency than Fbmsc in the future vascular related application.

  3. CRIPTO/GRP78 Signaling Maintains Fetal and Adult Mammary Stem Cells Ex Vivo

    PubMed Central

    Spike, Benjamin T.; Kelber, Jonathan A.; Booker, Evan; Kalathur, Madhuri; Rodewald, Rose; Lipianskaya, Julia; La, Justin; He, Marielle; Wright, Tracy; Klemke, Richard; Wahl, Geoffrey M.; Gray, Peter C.

    2014-01-01

    Summary Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks CRIPTO-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the CRIPTO/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers. PMID:24749068

  4. [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.

  5. Adipose-derived adult stem cells: available technologies for potential clinical regenerative applications in dentistry.

    PubMed

    Catalano, Enrico; Cochis, Andrea; Varoni, Elena; Rimondini, Lia; Carrassi, Antonio; Azzimonti, Barbara

    2013-01-01

    Tissue homeostasis depends closely on the activity and welfare of adult stem cells. These cells represent a promising tool for biomedical research since they can aid in treatment and promote the regeneration of damaged organs in many human disorders. Adult stem cells indefinitely preserve their ability to self-renew and differentiate into various phenotypes; this capacity could be promoted in vitro by particular culture conditions (differentiation media) or spontaneously induced in vivo by exploiting the biochemical and mechanical properties of the tissue in which the stem cells are implanted. Among the different sources of adult stem cells, adipose tissue is an attractive possibility thanks to its ready availability and the standard extraction techniques at our disposal today. This review discusses the isolation, characterization, and differentiation of human adipose-derived adult stem cells, as well as regeneration strategies, therapeutic uses, and adverse effects of their delivery. In particular, since oral disorders (e.g., trauma, erosion, and chronic periodontitis) often cause the loss of dental tissue along with functional, phonetic, and aesthetic impairment, this review focuses on the application of human adipose-derived adult stem cells, alone or in combination with biomaterials, in treating oral diseases.

  6. Does the adult human ciliary body epithelium contain "true" retinal stem cells?

    PubMed

    Frøen, Rebecca; Johnsen, Erik O; Nicolaissen, Bjørn; Facskó, Andrea; Petrovski, Goran; Moe, Morten C

    2013-01-01

    Recent reports of retinal stem cells being present in several locations of the adult eye have sparked great hopes that they may be used to treat the millions of people worldwide who suffer from blindness as a result of retinal disease or injury. A population of proliferative cells derived from the ciliary body epithelium (CE) has been considered one of the prime stem cell candidates, and as such they have received much attention in recent years. However, the true nature of these cells in the adult human eye has still not been fully elucidated, and the stem cell claim has become increasingly controversial in light of new and conflicting reports. In this paper, we will try to answer the question of whether the available evidence is strong enough for the research community to conclude that the adult human CE indeed harbors stem cells.

  7. Testosterone affects language areas of the adult human brain

    PubMed Central

    Hahn, Andreas; Kranz, Georg S.; Sladky, Ronald; Kaufmann, Ulrike; Ganger, Sebastian; Hummer, Allan; Seiger, Rene; Spies, Marie; Vanicek, Thomas; Winkler, Dietmar; Kasper, Siegfried; Windischberger, Christian; Swaab, Dick F.

    2016-01-01

    Abstract Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high‐dose hormone application in adult female‐to‐male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel‐based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting‐state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone‐dependent neuroplastic adaptations in adulthood within language‐specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738–1748, 2016. © 2016 Wiley Periodicals, Inc. PMID:26876303

  8. Experimental induction of corpora amylacea in adult rat brain.

    PubMed

    Schipper, H M

    1998-10-01

    Corpora amylacea (CA) are glycoproteinaceous inclusions that accumulate in astroglia and other brain cells as a function of advancing age and, to an even greater extent, in several human neurodegenerative conditions. The mechanisms responsible for their biogenesis and their subcellular origin(s) remain unclear. We previously demonstrated that the sulfhydryl agent, cysteamine (CSH), promotes the accumulation of CA-like inclusions in cultured rat astroglia. In the present study, we show that subcutaneous administration of CSH to adult rats (150 mg/kg for 6 weeks followed by a 5-week drug-washout period) elicits the accumulation of CA in many cortical and subcortical brain regions. As in the aging human brain and in CSH-treated rat astrocyte cultures, the inclusions are periodic acid-Schiff -positive and are consistently immunostained with antibodies directed against mitochondrial epitopes and ubiquitin. Our findings support our contention that mitochondria are important structural precursors of CA, and that CSH accelerates aging-like processes in rat astroglia both in vitro and in the intact brain.

  9. Testosterone affects language areas of the adult human brain.

    PubMed

    Hahn, Andreas; Kranz, Georg S; Sladky, Ronald; Kaufmann, Ulrike; Ganger, Sebastian; Hummer, Allan; Seiger, Rene; Spies, Marie; Vanicek, Thomas; Winkler, Dietmar; Kasper, Siegfried; Windischberger, Christian; Swaab, Dick F; Lanzenberger, Rupert

    2016-05-01

    Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high-dose hormone application in adult female-to-male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel-based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting-state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone-dependent neuroplastic adaptations in adulthood within language-specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738-1748, 2016. © 2016 Wiley Periodicals, Inc.

  10. Roles for oestrogen receptor β in adult brain function.

    PubMed

    Handa, R J; Ogawa, S; Wang, J M; Herbison, A E

    2012-01-01

    Oestradiol exerts a profound influence upon multiple brain circuits. For the most part, these effects are mediated by oestrogen receptor (ER)α. We review here the roles of ERβ, the other ER isoform, in mediating rodent oestradiol-regulated anxiety, aggressive and sexual behaviours, the control of gonadotrophin secretion, and adult neurogenesis. Evidence exists for: (i) ERβ located in the paraventricular nucleus underpinning the suppressive influence of oestradiol on the stress axis and anxiety-like behaviour; (ii) ERβ expressed in gonadotrophin-releasing hormone neurones contributing to oestrogen negative-feedback control of gonadotrophin secretion; (iii) ERβ controlling the offset of lordosis behaviour; (iv) ERβ suppressing aggressive behaviour in males; (v) ERβ modulating responses to social stimuli; and (vi) ERβ in controlling adult neurogenesis. This review highlights two major themes; first, ERβ and ERα are usually tightly inter-related in the oestradiol-dependent control of a particular brain function. For example, even though oestradiol feedback to control reproduction occurs principally through ERα-dependent mechanisms, modulatory roles for ERβ also exist. Second, the roles of ERα and ERβ within a particular neural network may be synergistic or antagonistic. Examples of the latter include the role of ERα to enhance, and ERβ to suppress, anxiety-like and aggressive behaviours. Splice variants such as ERβ2, acting as dominant negative receptors, are of further particular interest because their expression levels may reflect preceeding oestradiol exposure of relevance to oestradiol replacement therapy. Together, this review highlights the predominant modulatory, but nonetheless important, roles of ERβ in mediating the many effects of oestradiol upon adult brain function.

  11. 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.

  12. Stem Cells

    MedlinePlus

    Stem cells are cells with the potential to develop into many different types of cells in the body. ... the body. There are two main types of stem cells: embryonic stem cells and adult stem cells. Stem ...

  13. Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis.

    PubMed

    Encinas, Juan M; Sierra, Amanda

    2012-02-14

    Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.

  14. Efficient and Rapid Derivation of Primitive Neural Stem Cells and Generation of Brain Subtype Neurons From Human Pluripotent Stem Cells

    PubMed Central

    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

    2013-01-01

    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. PMID:24113065

  15. Hour-Long Nap May Boost Brain Function in Older Adults

    MedlinePlus

    ... fullstory_162923.html Hour-Long Nap May Boost Brain Function in Older Adults Linked to improved memory and ... during the day had any effects on their brain function. Nearly 60 percent of the people regularly napped ...

  16. BRAIN STEM STIMULATION AND ETHOLOGICAL STUDIES ON BIRDS.

    DTIC Science & Technology

    BIRDS, BEHAVIOR, BRAIN , STIMULATION (PHYSIOLOGY), PHYSIOLOGY, ADAPTATION(PHYSIOLOGY), ECOLOGY, THRESHOLDS(PHYSIOLOGY), REPRODUCTION(PHYSIOLOGY), RELAXATION(PHYSIOLOGY), POSTURE(PHYSIOLOGY), MOTION, FOOD.

  17. Neural stem cells improve neuronal survival in cultured postmortem brain tissue from aged and Alzheimer patients

    PubMed Central

    Wu, L; Sluiter, A A; Guo, Ho-fu; Balesar, R A; Swaab, D F; Zhou, Jiang-Ning; Verwer, R W H

    2008-01-01

    Abstract Neurodegenerative diseases are progressive and incurable and are becoming ever more prevalent. To study whether neural stem cell can reactivate or rescue functions of impaired neurons in the human aging and neurodegenerating brain, we co-cultured postmortem slices from Alzheimer patients and control participants with rat embryonic day 14 (E14) neural stem cells. Viability staining based on the exclusion of ethidium bromide by intact plasma membranes showed that there were strikingly more viable cells and fewer dead cells in slices co-cultured with neural stem cells than in untreated slices. The presence of Alzheimer pathology in the brain slices did not influence this effect, although the slices from Alzheimer patients, in general, contained fewer viable cells. Co-culturing with rat E14 fibroblasts did not improve the viability of neurons in the human brain slices. Since the human slices and neural stem cells were separated by a membrane during co-culturing our data show for the first time that neural stem cells release diffusible factors that may improve the survival of aged and degenerating neurons in human brains. PMID:18088384

  18. Microenvironmental determinants of adult neural stem cell proliferation and lineage commitment in the healthy and injured central nervous system.

    PubMed

    Moyse, Emmanuel; Segura, Stéphanie; Liard, Oliver; Mahaut, Stéphanie; Mechawar, Naguib

    2008-09-01

    The discovery of neural stem cells (NSC) which ensure continuous neurogenesis in the adult mammalian brain, has led to a conceptual revolution in basic neuroscience and to high hopes for clinical nervous tissue repair. However, several research issues remain to address before neural stem cells can be harnessed for regenerative therapies. The presence of NSC in a nervous structure is demonstrated in vitro by primary culture of dissociated adult nervous tissue in the presence of the specific mitogens EGF and bFGF. This leads to spherical masses of proliferating cells endowed with capacities for self-renewal and, after growth factor removal, differentiation into the three characteristic cell types of nervous tissue (neurons, astrocytes, oligodendrocytes). In vivo, neurogenesis per se, i.e. production of new neurons, occurs only in a small subset of NSC-endowed structures. The production of oligodendrocytes, i.e. myelinating glial cells, is similarly restricted. Such in vivo restrictions were formally demonstrated to arise from the tissular microenvironnement, which led to the emerging concept of "neurogenic niche". In this context, major challenges now consist in identifying the nature of tissue-specific extracellular signals that determine lineage commitment of NSC progeny, understanding why NSCs display weak in vivo reactivity to lesions compared to other stem cell types in adults, and identifying the factors behind the very high resistance to tumorigenesis displayed by NSCs. Altogether, the current data offer hope for the future use of adult NSCs in regenerative therapies, provided that tissue-specific signals are identified in view of counteracting the intrinsic repression of new cell genesis and/or stimulating endogenous NSC recruitment to lesion sites.

  19. Evaluation of an automatic brain segmentation method developed for neonates on adult MR brain images

    NASA Astrophysics Data System (ADS)

    Moeskops, Pim; Viergever, Max A.; Benders, Manon J. N. L.; Išgum, Ivana

    2015-03-01

    Automatic brain tissue segmentation is of clinical relevance in images acquired at all ages. The literature presents a clear distinction between methods developed for MR images of infants, and methods developed for images of adults. The aim of this work is to evaluate a method developed for neonatal images in the segmentation of adult images. The evaluated method employs supervised voxel classification in subsequent stages, exploiting spatial and intensity information. Evaluation was performed using images available within the MRBrainS13 challenge. The obtained average Dice coefficients were 85.77% for grey matter, 88.66% for white matter, 81.08% for cerebrospinal fluid, 95.65% for cerebrum, and 96.92% for intracranial cavity, currently resulting in the best overall ranking. The possibility of applying the same method to neonatal as well as adult images can be of great value in cross-sectional studies that include a wide age range.

  20. New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains.

    PubMed

    Miyata, Seiji

    2015-01-01

    The blood-brain barrier (BBB) generally consists of endothelial tight junction barriers that prevent the free entry of blood-derived substances, thereby maintaining the extracellular environment of the brain. However, the circumventricular organs (CVOs), which are located along the midlines of the brain ventricles, lack these endothelial barriers and have fenestrated capillaries; therefore, they have a number of essential functions, including the transduction of information between the blood circulation and brain. Previous studies have demonstrated the extensive contribution of the CVOs to body fluid and thermal homeostasis, energy balance, the chemoreception of blood-derived substances, and neuroinflammation. In this review, recent advances have been discussed in fenestrated capillary characterization and dynamic tissue reconstruction accompanied by angiogenesis and neurogliogenesis in the sensory CVOs of adult brains. The sensory CVOs, including the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), have size-selective and heterogeneous vascular permeabilities. Astrocyte-/tanycyte-like neural stem cells (NSCs) sense blood- and cerebrospinal fluid-derived information through the transient receptor potential vanilloid 1, a mechanical/osmotic receptor, Toll-like receptor 4, a lipopolysaccharide receptor, and Nax, a Na-sensing Na channel. They also express tight junction proteins and densely and tightly surround mature neurons to protect them from blood-derived neurotoxic substances, indicating that the NSCs of the CVOs perform BBB functions while maintaining the capacity to differentiate into new neurons and glial cells. In addition to neurogliogenesis, the density of fenestrated capillaries is regulated by angiogenesis, which is accompanied by the active proliferation and sprouting of endothelial cells. Vascular endothelial growth factor (VEGF) signaling may be involved in angiogenesis and neurogliogenesis, both of

  1. Methylene Blue (Tetramethylthionine Chloride) Influences the Mobility of Adult Neural Stem Cells: A Potentially Novel Therapeutic Mechanism of a Therapeutic Approach in the Treatment of Alzheimer's Disease.

    PubMed

    van der Ven, Amelie T; Pape, Julius C; Hermann, Dirk; Schloesser, Robert; Genius, Just; Fischer, Nadine; Mößner, Rainald; Scherbaum, Norbert; Wiltfang, Jens; Rujescu, Dan; Benninghoff, Jens

    2017-01-01

    An interest in neurogenesis in the adult human brain as a relevant and targetable process has emerged as a potential treatment option for Alzheimer's disease and other neurodegenerative conditions. The aim of this study was to investigate the effects of tetramethylthionine chloride (methylene blue, MB) on properties of adult murine neural stem cells. Based on recent clinical studies, MB has increasingly been discussed as a potential treatment for Alzheimer's disease. While no differences in the proliferative capacity were identified, a general potential of MB in modulating the migratory capacity of adult neural stem cells was indicated in a cell mobility assay. To our knowledge, this is the first time that MB could be associated with neural mobility. The results of this study add insight to the spectrum of features of MB within the central nervous system and may be helpful for understanding the molecular mechanisms underlying a potential therapeutic effect of MB.

  2. Expression of polysialylated neural cell adhesion molecules on adult stem cells after neuronal differentiation of inner ear spiral ganglion neurons.

    PubMed

    Park, Kyoung Ho; Yeo, Sang Won; Troy, Frederic A

    2014-10-17

    During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia-NCAMs) modulate cell-cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia-NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb's to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell-cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.

  3. Doublecortin in Oligodendrocyte Precursor Cells in the Adult Mouse Brain

    PubMed Central

    Boulanger, Jenna J.; Messier, Claude

    2017-01-01

    Key Points Oligodendrocyte precursor cells express doublecortin, a microtubule-associated protein.Oligodendrocyte precursor cells express doublecortin, but at a lower level of expression than in neuronal precursor.Doublecortin is not associated with a potential immature neuronal phenotype in Oligodendrocyte precursor cells. Oligodendrocyte precursor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during embryogenesis and early stages of post-natal life. OPCs continue to divide throughout adulthood and some eventually differentiate into oligodendrocytes in response to demyelinating lesions. There is growing evidence that OPCs are also involved in activity-driven de novo myelination of previously unmyelinated axons and myelin remodeling in adulthood. Considering these roles in the adult brain, OPCs are likely mobile cells that can migrate on some distances before they differentiate into myelinating oligodendrocytes. A number of studies have noted that OPCs express doublecortin (DCX), a microtubule-associated protein expressed in neural precursor cells and in migrating immature neurons. Here we describe the distribution of DCX in OPCs. We found that almost all OPCs express DCX, but the level of expression appears to be much lower than what is found in neural precursor. We found that DCX is downregulated when OPCs start expressing mature oligodendrocyte markers and is absent in myelinating oligodendrocytes. DCX does not appear to signal an immature neuronal phenotype in OPCs in the adult mouse brain. Rather, it could be involved either in cell migration, or as a marker of an immature oligodendroglial cell phenotype.

  4. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

    PubMed Central

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  5. Wildtype adult stem cells, unlike tumor cells, are resistant to cellular damages in Drosophila.

    PubMed

    Ma, Meifang; Zhao, Hang; Zhao, Hanfei; Binari, Richard; Perrimon, Norbert; Li, Zhouhua

    2016-03-15

    Adult stem cells or residential progenitor cells are critical to maintain the structure and function of adult tissues (homeostasis) throughout the lifetime of an individual. Mis-regulation of stem cell proliferation and differentiation often leads to diseases including cancer, however, how wildtype adult stem cells and cancer cells respond to cellular damages remains unclear. We find that in the adult Drosophila midgut, intestinal stem cells (ISCs), unlike tumor intestinal cells, are resistant to various cellular damages. Tumor intestinal cells, unlike wildtype ISCs, are easily eliminated by apoptosis. Further, their proliferation is inhibited upon autophagy induction, and autophagy-mediated tumor inhibition is independent of caspase-dependent apoptosis. Interestingly, inhibition of tumorigenesis by autophagy is likely through the sequestration and degradation of mitochondria, as compromising mitochondria activity in these tumor models mimics the induction of autophagy and increasing the production of mitochondria alleviates the tumor-suppression capacity of autophagy. Together, these data demonstrate that wildtype adult stem cells and tumor cells show dramatic differences in sensitivity to cellular damages, thus providing potential therapeutic implications targeting tumorigenesis.

  6. Conflict rationalisation: how family members cope with a diagnosis of brain stem death.

    PubMed

    Long, Tracy; Sque, Magi; Addington-Hall, Julia

    2008-07-01

    Brain death, whether it be brain stem death in the UK, or whole-brain death in the USA, is a prerequisite for heart-beating organ donation. Understanding how brain death is perceived by family members approached about organ donation, its significance to them, and if it is accepted by them, are, therefore, important issues to explore as biomedicine expands the range of end of life technologies that blur the demarcation between life and death. To explore the concept of brain stem death and its meaning to family members the following research questions were posed: (i) what does the diagnosis of death based on brain stem testing mean to bereaved family members who have been approached and asked to consider a donation from a deceased relative, and (ii) how do family members understand the concept of brain stem death? To address these research questions, a secondary analysis of 28 interviews sorted from two primary datasets was carried out. The primary datasets contained longitudinal and cross-sectional interviews carried out in the UK with family members who had been approached about organ donation and agreed to donate their relatives' organs. Data analysis was guided by constructionist grounded theory method and resulted in the theory of Paradoxical Death. In this process, family members and health professionals engage in a series of practical and psychological activities aimed at rationalising real or potential emotional and cognitive conflict resulting from a brain-based diagnosis of death, whilst faced with the physical image of a functioning body. Rationalising emotional and cognitive conflict is how family members and health professionals appeared to process this paradoxical death, a death that is contrary to conventional opinion.

  7. Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells.

    PubMed

    Yamada, Mitsutoshi; Johannesson, Bjarki; Sagi, Ido; Burnett, Lisa Cole; Kort, Daniel H; Prosser, Robert W; Paull, Daniel; Nestor, Michael W; Freeby, Matthew; Greenberg, Ellen; Goland, Robin S; Leibel, Rudolph L; Solomon, Susan L; Benvenisty, Nissim; Sauer, Mark V; Egli, Dieter

    2014-06-26

    The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes.

  8. A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages.

    PubMed

    Pearson, Bret J; Sánchez Alvarado, Alejandro

    2010-01-01

    The functions of adult stem cells and tumor suppressor genes are known to intersect. However, when and how tumor suppressors function in the lineages produced by adult stem cells is unknown. With a large population of stem cells that can be manipulated and studied in vivo, the freshwater planarian is an ideal system with which to investigate these questions. Here, we focus on the tumor suppressor p53, homologs of which have no known role in stem cell biology in any invertebrate examined thus far. Planaria have a single p53 family member, Smed-p53, which is predominantly expressed in newly made stem cell progeny. When Smed-p53 is targeted by RNAi, the stem cell population increases at the expense of progeny, resulting in hyper-proliferation. However, ultimately the stem cell population fails to self-renew. Our results suggest that prior to the vertebrates, an ancestral p53-like molecule already had functions in stem cell proliferation control and self-renewal.

  9. Physics strategies for sparing neural stem cells during whole-brain radiation treatments

    SciTech Connect

    Kirby, Neil; Chuang, Cynthia; Pouliot, Jean; Hwang, Andrew; Barani, Igor J.

    2011-10-15

    Purpose: Currently, there are no successful long-term treatments or preventive strategies for radiation-induced cognitive impairments, and only a few possibilities have been suggested. One such approach involves reducing the dose to neural stem cell compartments (within and outside of the hippocampus) during whole-brain radiation treatments for brain metastases. This study investigates the fundamental physics issues associated with the sparing of neural stem cells during photon radiotherapy for brain metastases. Methods: Several factors influence the stem cell dose: intracranial scattering, collimator leakage, beam energy, and total number of beams. The relative importance of these factors is investigated through a set of radiation therapy plans, which are all variations of an initial 6 MV intensity-modulated radiation therapy (IMRT) plan designed to simultaneously deliver a whole-brain dose of 30 Gy and maximally reduce stem cell compartment dose. Additionally, an in-house leaf segmentation algorithm was developed that utilizes jaw motion to minimize the collimator leakage. Results: The plans are all normalized such that 50% of the PTV receives 30 Gy. For the initial 6 MV IMRT plan, 50% of the stem cells receive a dose greater than 6.3 Gy. Calculations indicate that 3.6 Gy of this dose originates from intracranial scattering. The jaw-tracking segmentation algorithm, used in conjunction with direct machine parameter optimization, reduces the 50% stem cell dose to 4.3 and 3.7 Gy for 6 and 10 MV treatment beams, respectively. Conclusions: Intracranial scattering alone is responsible for a large dose contribution to the stem cell compartment. It is, therefore, important to minimize other contributing factors, particularly the collimator leakage, to maximally reduce dose to these critical structures. The use of collimator jaw tracking in conjunction with modern collimators can minimize this leakage.

  10. Electrophysiological Properties of Subventricular Zone Cells in Adult Mouse Brain

    PubMed Central

    Lai, Bin; Mao, Xiao Ou; Xie, Lin; Chang, Su-Youne; Xiong, Zhi-Gang; Jin, Kunlin; Greenberg, David A.

    2010-01-01

    The subventricular zone (SVZ) is a principal site of adult neurogenesis and appears to participate in the brain’s response to injury. Thus, measures that enhance SVZ neurogenesis may have a role in treatment of neurological disease. To better characterize SVZ cells and identify potential targets for therapeutic intervention, we studied electrophysiological properties of SVZ cells in adult mouse brain slices using patch-clamp techniques. Electrophysiology was correlated with immunohistochemical phenotype by injecting cells with lucifer yellow and by studying transgenic mice carrying green fluorescent protein under control of the doublecortin (DCX) or glial fibrillary acidic protein (GFAP) promoter. We identified five types of cells in the adult mouse SVZ: type 1 cells, with 4-aminopyridine (4-AP)/tetraethylammonium (TEA)-sensitive and CdCl2-sensitive inward currents; type 2 cells, with Ca2+-sensitive K+ and both 4-AP/TEA-sensitive and -insensitive currents; type 3 cells, with 4-AP/TEA-sensitive and -insensitive and small Na+ currents; type 4 cells, with slowly activating, large linear outward current and sustained outward current without fast-inactivating component; and type 5 cells, with a large outward rectifying current with a fast inactivating component. Type 2 and 3 cells expressed DCX, types 4 and 5 cells expressed GFAP, and type 1 cells expressed neither. We propose that SVZ neurogenesis involves a progression of electrophysiological cell phenotypes from types 4 and 5 cells (astrocytes) to type 1 cells (neuronal progenitors) to types 2 and 3 cells (nascent neurons), and that drugs acting on. ion channels expressed during neurogenesis might promote therapeutic neurogenesis in the injured brain. PMID:20434436

  11. Diversity of Epithelial Stem Cell Types in Adult Lung

    PubMed Central

    Li, Feng; He, Jinxi; Wei, Jun; Cho, William C.; Liu, Xiaoming

    2015-01-01

    Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays, in vitro and/or ex vivo models, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer. PMID:25810726

  12. Neural stem cells: generating and regenerating the brain.

    PubMed

    Gage, Fred H; Temple, Sally

    2013-10-30

    One of the landmark events of the past 25 years in neuroscience research was the establishment of neural stem cells (NSCs) as a life-long source of neurons and glia, a concept that shattered the dogma that the nervous system lacked regenerative power. Stem cells afford the plasticity to generate, repair, and change nervous system function. Combined with reprogramming technology, human somatic cell-derived NSCs and their progeny can model neurological diseases with improved accuracy. As technology advances, we anticipate further important discoveries and novel therapies based on the knowledge and application of these powerful cells.

  13. Doublecortin expression in the normal and epileptic adult human brain.

    PubMed

    Liu, Y W J; Curtis, M A; Gibbons, H M; Mee, E W; Bergin, P S; Teoh, H H; Connor, B; Dragunow, M; Faull, R L M

    2008-12-01

    Mesial temporal lobe epilepsy (MTLE) is a neurological disorder associated with spontaneous recurrent complex partial seizures and hippocampal sclerosis. Although increased hippocampal neurogenesis has been reported in animal models of MTLE, increased neurogenesis has not been reported in the hippocampus of adult human MTLE cases. Here we showed that cells expressing doublecortin (Dcx), a microtubule-associated protein expressed in migrating neuroblasts, were present in the hippocampus and temporal cortex of the normal and MTLE adult human brain. In particular, increased numbers of Dcx-positive cells were observed in the epileptic compared with the normal temporal cortex. Importantly, 56% of Dcx-expressing cells in the epileptic temporal cortex coexpressed both the proliferative cell marker, proliferating cell nuclear antigen and early neuronal marker, TuJ1, suggesting that they may be newly generated neurons. A subpopulation of Dcx-positive cells in the epileptic temporal cortex also coexpressed the mature neuronal marker, NeuN, suggesting that epilepsy may promote the generation of new neurons in the temporal cortex. This study has identified, for the first time, a novel population of Dcx-positive cells in the adult human temporal cortex that can be upregulated by epilepsy and thus, raises the possibility that these cells may have functional significance in the pathophysiology of epilepsy.

  14. Fetal and adult liver stem cells for liver regeneration and tissue engineering.

    PubMed

    Fiegel, H C; Lange, Claudia; Kneser, U; Lambrecht, W; Zander, A R; Rogiers, X; Kluth, D

    2006-01-01

    For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches.

  15. Typography manipulations can affect priming of word stem completion in older and younger adults.

    PubMed

    Gibson, J M; Brooks, J O; Friedman, L; Yesavage, J A

    1993-12-01

    The experiments reported here investigated whether changes of typography affected priming of word stem completion performance in older and younger adults. Across all experiments, the typeface in which a word appeared at presentation either did or did not match that of its 3-letter stem at test. In Experiment 1, no significant evidence of a typography effect was found when words were presented with a sentence judgment or letter judgment task. However, subsequent experiments revealed that, in both older and younger adults, only words presented with a syllable judgment task gave rise to the typography effect (Experiments 2-4). Specifically, performance was greater, when the presentation and test typeface matched than when they did not. Experiment 5, which used stem-cued recall, did not reveal a difference between syllable and letter judgment tasks. These findings highlight the complex nature of word stem completion performance.

  16. Purines regulate adult brain subventricular zone cell functions: contribution of reactive astrocytes.

    PubMed

    Boccazzi, Marta; Rolando, Chiara; Abbracchio, Maria P; Buffo, Annalisa; Ceruti, Stefania

    2014-03-01

    Brain injuries modulate activation of neural stem cells (NSCs) in the adult brain. In pathological conditions, the concentrations of extracellular nucleotides (eNTs) raise several folds, contribute to reactive gliosis, and possibly directly affect subventricular zone (SVZ) cell functioning. Among eNTs and derived metabolites, the P2Y1 receptor agonist ADP strongly promotes astrogliosis and might also influence SVZ progenitor activity. Here, we tested the ability of the stable P2Y1 agonist adenosine 5'-O-(2-thiodiphosphate) (ADPβS) to control adult NSC functions both in vitro and in vivo, with a focus on the possible effects exerted by reactive astrocytes. In the absence of growth factors, ADPβS promoted proliferation and differentiation of SVZ progenitors. Moreover, ADPβS-activated astrocytes markedly changed the pattern of released cytokines and chemokines, and strongly modulated neurosphere-forming capacity of SVZ progenitors. Notably, a significant enhancement in proliferation was observed when SVZ cells, initially grown in the supernatant of astrocytes exposed to ADPβS, were shifted to normal medium. In vivo, ADPβS administration in the lateral ventricle of adult mice by osmotic minipumps caused diffused reactive astrogliosis, and a strong response of SVZ progenitors. Indeed, proliferation of glial fibrillary acidic protein-positive NSCs increased and led to a significant expansion of SVZ transit-amplifying progenitors and neuroblasts. Lineage tracing experiments performed in the GLAST::CreERT2;Rosa-YFP transgenic mice further demonstrated that ADPβS promoted proliferation of glutamate/aspartate transporter-positive progenitors and sustained their progression toward the generation of rapidly dividing progenitors. Altogether, our results show that the purinergic system crucially affects SVZ progenitor activities both directly and through the involvement of reactive astrocytes.

  17. Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

    PubMed Central

    West, John D; Dorà, Natalie J; Collinson, J Martin

    2015-01-01

    In this review we evaluate evidence for three different hypotheses that explain how the corneal epithelium is maintained. The limbal epithelial stem cell (LESC) hypothesis is most widely accepted. This proposes that stem cells in the basal layer of the limbal epithelium, at the periphery of the cornea, maintain themselves and also produce transient (or transit) amplifying cells (TACs). TACs then move centripetally to the centre of the cornea in the basal layer of the corneal epithelium and also replenish cells in the overlying suprabasal layers. The LESCs maintain the corneal epithelium during normal homeostasis and become more active to repair significant wounds. Second, the corneal epithelial stem cell (CESC) hypothesis postulates that, during normal homeostasis, stem cells distributed throughout the basal corneal epithelium, maintain the tissue. According to this hypothesis, LESCs are present in the limbus but are only active during wound healing. We also consider a third possibility, that the corneal epithelium is maintained during normal homeostasis by proliferation of basal corneal epithelial cells without any input from stem cells. After reviewing the published evidence, we conclude that the LESC and CESC hypotheses are consistent with more of the evidence than the third hypothesis, so we do not consider this further. The LESC and CESC hypotheses each have difficulty accounting for one main type of evidence so we evaluate the two key lines of evidence that discriminate between them. Finally, we discuss how lineage-tracing experiments have begun to resolve the debate in favour of the LESC hypothesis. Nevertheless, it also seems likely that some basal corneal epithelial cells can act as long-term progenitors if limbal stem cell function is compromised. Thus, this aspect of the CESC hypothesis may have a lasting impact on our understanding of corneal epithelial maintenance, even if it is eventually shown that stem cells are restricted to the limbus as proposed

  18. Transient severe brain stem depression during intraarterial papaverine infusion for cerebral vasospasm

    SciTech Connect

    Barr, J.D.; Mathis, J.M.; Horton, J.A. )

    1994-04-01

    A 63-yr-old woman had severe, symptomatic cerebral vasospasm secondary to subarachnoid hemorrhage. We initiated simultaneous infusions of papaverine into her left vertebral and left internal carotid arteries. Twenty-five minutes after the fusions had begun, the patient had a transient reaction of respiratory arrest followed by rapid, progressive loss of brain stem function. 28 refs., 1 fig.

  19. An essential and evolutionarily conserved role of protein arginine methyltransferase 1 for adult intestinal stem cells during postembryonic development.

    PubMed

    Matsuda, Hiroki; Shi, Yun-Bo

    2010-11-01

    Organ-specific adult stem cells are critical for the homeostasis of adult organs and organ repair and regeneration. Unfortunately, it has been difficult to investigate the origins of these stem cells and the mechanisms of their development, especially in mammals. Intestinal remodeling during frog metamorphosis offers a unique opportunity for such studies. During the transition from an herbivorous tadpole to a carnivorous frog, the intestine is completely remodeled as the larval epithelial cells undergo apoptotic degeneration and are replaced by adult epithelial cells developed de novo. The entire metamorphic process is under the control of thyroid hormone, making it possible to control the development of the adult intestinal stem cells. Here, we show that the thyroid hormone receptor-coactivator protein arginine methyltransferase 1 (PRMT1) is upregulated in a small number of larval epithelial cells and that these cells dedifferentiate to become the adult stem cells. More importantly, transgenic overexpression of PRMT1 leads to increased adult stem cells in the intestine, and conversely, knocking down the expression of endogenous PRMT1 reduces the adult stem cell population. In addition, PRMT1 expression pattern during zebrafish and mouse development suggests that PRMT1 may play an evolutionally conserved role in the development of adult intestinal stem cells throughout vertebrates. These findings are not only important for the understanding of organ-specific adult stem cell development but also have important implications in regenerative medicine of the digestive tract.

  20. Chemokine-mobilized adult stem cells; defining a better hematopoietic graft.

    PubMed

    Pelus, L M; Fukuda, S

    2008-03-01

    Stem cell research is currently focused on totipotent stem cells and their therapeutic potential, however adult stem cells, while restricted to differentiation within their tissue or origin, also have therapeutic utility. Transplantation with bone marrow hematopoietic stem cells (HSC) has been used for curative therapy for decades. More recently, alternative sources of HSC, particularly those induced to exit marrow or mobilize to peripheral blood by G-CSF, have become the most widely used hematopoietic graft and show significant superiority to marrow HSC. The chemokine/chemokine receptor axis also mobilizes HSC that occurs more rapidly than with G-CSF. In mice, the HSC and progenitor cells (HPC) mobilized by the CXCR2 receptor agonist GRObeta can be harvested within minutes of administration and show significantly lower levels of apoptosis, enhanced homing to marrow, expression of more activated integrin receptors and superior repopulation kinetics and more competitive engraftment than the equivalent cells mobilized by G-CSF. These characteristics suggest that chemokine axis-mobilized HSC represent a population of adult stem cells distinct from those mobilized by G-CSF, with superior therapeutic potential. It remains to be determined if the chemokine mobilization axis can be harnessed to mobilize other populations of unique adult stem cells with clinical utility.

  1. Concise Review: Quiescence in Adult Stem Cells: Biological Significance and Relevance to Tissue Regeneration.

    PubMed

    Rumman, Mohammad; Dhawan, Jyotsna; Kassem, Moustapha

    2015-10-01

    Adult stem cells (ASCs) are tissue resident stem cells responsible for tissue homeostasis and regeneration following injury. In uninjured tissues, ASCs exist in a nonproliferating, reversibly cell cycle-arrested state known as quiescence or G0. A key function of the quiescent state is to preserve stemness in ASCs by preventing precocious differentiation, and thus maintaining a pool of undifferentiated ASCs. Recent evidences suggest that quiescence is an actively maintained state and that excessive or defective quiescence may lead to compromised tissue regeneration or tumorigenesis. The aim of this review is to provide an update regarding the biological mechanisms of ASC quiescence and their role in tissue regeneration.

  2. In Vitro Differentiation of Embryonic and Adult Stem Cells into Hepatocytes: State of the Art

    PubMed Central

    Snykers, Sarah; De Kock, Joery; Rogiers, Vera; Vanhaecke, Tamara

    2009-01-01

    Stem cells are a unique source of self-renewing cells within the human body. Before the end of the last millennium, adult stem cells, in contrast to their embryonic counterparts, were considered to be lineage-restricted cells or incapable of crossing lineage boundaries. However, the unique breakthrough of muscle and liver regeneration by adult bone marrow stem cells at the end of the 1990s ended this long-standing paradigm. Since then, the number of articles reporting the existence of multipotent stem cells in skin, neuronal tissue, adipose tissue, and bone marrow has escalated, giving rise, both in vivo and in vitro, to cell types other than their tissue of origin. The phenomenon of fate reprogrammation and phenotypic diversification remains, though, an enigmatic and rare process. Understanding how to control both proliferation and differentiation of stem cells and their progeny is a challenge in many fields, going from preclinical drug discovery and development to clinical therapy. In this review, we focus on current strategies to differentiate embryonic, mesenchymal(-like), and liver stem/progenitor cells into hepatocytes in vitro. Special attention is paid to intracellular and extracellular signaling, genetic modification, and cell-cell and cell-matrix interactions. In addition, some recommendations are proposed to standardize, optimize, and enrich the in vitro production of hepatocyte-like cells out of stem/progenitor cells. PMID:19056906

  3. Endothelial juxtaposition of distinct adult stem cells activates angiogenesis signaling molecules in endothelial cells.

    PubMed

    Mohammadi, Elham; Nassiri, Seyed Mahdi; Rahbarghazi, Reza; Siavashi, Vahid; Araghi, Atefeh

    2015-12-01

    Efficacy of therapeutic angiogenesis needs a comprehensive understanding of endothelial cell (EC) function and biological factors and cells that interplay with ECs. Stem cells are considered the key components of pro- and anti-angiogenic milieu in a wide variety of physiopathological states, and interactions of EC-stem cells have been the subject of controversy in recent years. In this study, the potential effects of three tissue-specific adult stem cells, namely rat marrow-derived mesenchymal stem cells (rBMSCs), rat adipose-derived stem cells (rADSCs) and rat muscle-derived satellite cells (rSCs), on the endothelial activation of key angiogenic signaling molecules, including VEGF, Ang-2, VEGFR-2, Tie-2, and Tie2-pho, were investigated. Human umbilical vein endothelial cells (HUVECs) and rat lung microvascular endothelial cells (RLMECs) were cocultured with the stem cells or incubated with the stem cell-derived conditioned media on Matrigel. Following HUVEC-stem cell coculture, CD31-positive ECs were flow sorted and subjected to western blotting to analyze potential changes in the expression of the pro-angiogenic signaling molecules. Elongation and co-alignment of the stem cells were seen along the EC tubes in the EC-stem cell cocultures on Matrigel, with cell-to-cell dye communication in the EC-rBMSC cocultures. Moreover, rBMSCs and rADSCs significantly improved endothelial tubulogenesis in both juxtacrine and paracrine manners. These two latter stem cells dynamically up-regulated VEGF, Ang-2, VREGR-2, and Tie-2 but down-regulated Tie2-pho and the Tie2-pho/Tie-2 ratio in HUVECs. Induction of pro-angiogenic signaling in ECs by marrow- and adipose-derived MSCs further indicates the significance of stem cell milieu in angiogenesis dynamics.

  4. Phases I–III Clinical Trials Using Adult Stem Cells

    PubMed Central

    Sanz-Ruiz, Ricardo; Gutiérrez Ibañes, Enrique; Arranz, Adolfo Villa; Fernández Santos, María Eugenia; Fernández, Pedro L. Sánchez; Fernández-Avilés, Francisco

    2010-01-01

    First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field. PMID:21076533

  5. CILIA FORMATION IN THE ADULT CAT BRAIN AFTER PARGYLINE TREATMENT

    PubMed Central

    Milhaud, Monique; Pappas, George D.

    1968-01-01

    The brains of four adult cats treated with pargyline (a nonhydrazide monoaminoxidase inhibitor) were examined at both the light and electron microscopic levels. Formation of typical mature cilia with the 9 + 2 pattern was observed in neural cells in the following areas: habenula nuclei, interpeduncular nuclei, hippocampus, mammillary bodies, thalamus, and caudate nucleus. The most marked ciliation occurs in the habenula nuclei. In general, glial cells greatly predominate in the formation of cilia. It is not clear whether ciliation in the central nervous system is the direct result of pargyline or if it occurs indirectly as a result of inhibition of monoaminoxidase. These findings are compared with the serotonin effect on ciliation in the embryogenesis of lower forms. It is suggested that pharmacological stimulation of centriolar reproduction without subsequent mitosis may lead to ciliary formation. PMID:11905194

  6. A model for genomic imprinting in the social brain: adults.

    PubMed

    Ubeda, Francisco; Gardner, Andy

    2011-02-01

    Genomic imprinting refers to genes that are silenced when inherited via sperm or via egg. The silencing of genes conditional upon their parental origin requires an evolutionary explanation. The most widely accepted theory for the evolution of genomic imprinting-the kinship theory-argues that conflict between maternally inherited and paternally inherited genes over phenotypes with asymmetric effects on matrilineal and patrilineal kin results in self-imposed silencing of one of the copies. This theory has been applied to imprinting of genes expressed in the placenta, and infant brain determining the allocation of parental resources being the source of conflict parental promiscuity. However, there is growing evidence that imprinted genes are expressed in the postinfant brain where parental promiscuity per se is no longer a source of conflict. Here, we advance the kinship theory by developing an evolutionary model of genomic imprinting in adults, driven by intragenomic conflict over allocation to parental versus communal care. We consider the role of sex differences in dispersal and variance in reproductive success as sources of conflict. We predict that, in hominids and birds, parental care will be expressed by maternally inherited genes. In nonhominid mammals, we predict more diversity, with some mammals showing the same pattern and other showing the reverse. We use the model to interpret experimental data on imprinted genes in the house mouse: specifically, paternally expressed Peg1 and Peg3 genes, underlying maternal care, and maternally expressed Gnas and paternally expressed Gnasxl genes, underlying communal care. We also use the model to relate ancestral demography to contemporary imprinting disorders of adults, in humans and other taxa.

  7. Pluripotency of adult stem cells derived from human and rat pancreas

    NASA Astrophysics Data System (ADS)

    Kruse, C.; Birth, M.; Rohwedel, J.; Assmuth, K.; Goepel, A.; Wedel, T.

    Adult stem cells are undifferentiated cells found within fully developed tissues or organs of an adult individuum. Until recently, these cells have been considered to bear less self-renewal ability and differentiation potency compared to embryonic stem cells. In recent studies an undifferentiated cell type was found in primary cultures of isolated acini from exocrine pancreas termed pancreatic stellate cells. Here we show that pancreatic stellate-like cells have the capacity of extended self-renewal and are able to differentiate spontaneously into cell types of all three germ layers expressing markers for smooth muscle cells, neurons, glial cells, epithelial cells, chondrocytes and secretory cells (insulin, amylase). Differentiation and subsequent formation of three-dimensional cellular aggregates (organoid bodies) were induced by merely culturing pancreatic stellate-like cells in hanging drops. These cells were developed into stable, long-term, in vitro cultures of both primary undifferentiated cell lines as well as organoid cultures. Thus, evidence is given that cell lineages of endodermal, mesodermal, and ectodermal origin arise spontaneously from a single adult undifferentiated cell type. Based on the present findings it is assumed that pancreatic stellate-like cells are a new class of lineage uncommitted pluripotent adult stem cells with a remarkable self-renewal ability and differentiation potency. The data emphasize the versatility of adult stem cells and may lead to a reappraisal of their use for the treatment of inherited disorders or acquired degenerative diseases.

  8. Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps

    PubMed Central

    Broughton, Kathleen; Sussman, Mark A.

    2016-01-01

    Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells four years ago (Mohsin et al., Empowering adult stem cells for myocardial regeneration. Circ Res. 2011; 109(12):1415–1428) [1]. The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathologic injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating “state of affairs” in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: “Success will never be a big step in the future. Success is a small step taken just now.” PMID:26941423

  9. Emerging Insights for Better Delivery of Chemicals and Stem Cells to the Brain.

    PubMed

    Baig, Abdul Mannan

    2017-04-03

    The human central nervous system and its vascularity has evolved a complex yet useful barricade, called the blood-brain barrier. The understanding of this barrier and the transport proteins that allow a selective access across it remains fundamental in designing chemicals and molecules that could cross it and prove therapeutically beneficial. After the recent findings of the brain-lymphatic link and the movement of chemical molecules from the central nervous system into general circulation, the model of the blood-brain barrier needs to be revisited. Here the author intends to discuss the components of the blood-brain barrier, debate the novel routes of administration and delivery systems for the drugs and embryonic stem cells that could cross or bypass the blood-brain barrier in order to reach the central nervous system.

  10. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

    PubMed Central

    Oliva, Carolina A.; Vargas, Jessica Y.; Inestrosa, Nibaldo C.

    2013-01-01

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID:24348327

  11. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies.

    PubMed

    Oliva, Carolina A; Vargas, Jessica Y; Inestrosa, Nibaldo C

    2013-12-03

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.

  12. Origins of adult pigmentation: diversity in pigment stem cell lineages and implications for pattern evolution

    PubMed Central

    Spiewak, Jessica E.

    2014-01-01

    Summary Teleosts comprise about half of all vertebrate species and exhibit an extraordinary diversity of adult pigment patterns that function in shoaling, camouflage and mate choice and have played important roles in speciation. Here, we review recent studies that have identified several distinct neural crest lineages, with distinct genetic requirements, that give rise to adult pigment cells in fishes. These lineages include post-embryonic, peripheral nerve associated stem cells that generate black melanophores and iridescent iridophores, cells derived directly from embryonic neural crest cells that generate yellow-orange xanthophores, and bipotent stem cells that generate both melanophores and xanthophores. This complexity in adult chromatophore lineages has implications for our understanding of adult traits, melanoma, and the evolutionary diversification of pigment cell lineages and patterns. PMID:25421288

  13. Origins of adult pigmentation: diversity in pigment stem cell lineages and implications for pattern evolution.

    PubMed

    Parichy, David M; Spiewak, Jessica E

    2015-01-01

    Teleosts comprise about half of all vertebrate species and exhibit an extraordinary diversity of adult pigment patterns that function in shoaling, camouflage, and mate choice and have played important roles in speciation. Here, we review studies that have identified several distinct neural crest lineages, with distinct genetic requirements, that give rise to adult pigment cells in fishes. These lineages include post-embryonic, peripheral nerve-associated stem cells that generate black melanophores and iridescent iridophores, cells derived directly from embryonic neural crest cells that generate yellow-orange xanthophores, and bipotent stem cells that generate both melanophores and xanthophores. This complexity in adult chromatophore lineages has implications for our understanding of adult traits, melanoma, and the evolutionary diversification of pigment cell lineages and patterns.

  14. Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human iPSCs

    PubMed Central

    Srikanth, Priya; Young-Pearse, Tracy L.

    2014-01-01

    Seven years have passed since the initial report of the generation of induced pluripotent stem cells from adult humans, and in the intervening time the field of neuroscience has developed numerous disease models using this technology. Here, we review the progress in the field, and describe both the advantages and potential pitfalls of modeling neurodegenerative and neurodevelopmental diseases using this technology. PMID:24628482

  15. Does State Merit-Based Aid Stem Brain Drain?

    ERIC Educational Resources Information Center

    Zhang, Liang; Ness, Erik C.

    2010-01-01

    In this study, the authors use college enrollment and migration data to test the brain drain hypothesis. Their results suggest that state merit scholarship programs do indeed stanch the migration of "best and brightest" students to other states. In the aggregate and on average, the implementation of state merit aid programs increases the…

  16. NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain.

    PubMed

    Gampe, Kristine; Stefani, Jennifer; Hammer, Klaus; Brendel, Peter; Pötzsch, Alexandra; Enikolopov, Grigori; Enjyoji, Keiichi; Acker-Palmer, Amparo; Robson, Simon C; Zimmermann, Herbert

    2015-01-01

    Nerve cells are continuously generated from stem cells in the adult mammalian subventricular zone (SVZ) and hippocampal dentate gyrus. We have previously noted that stem/progenitor cells in the SVZ and the subgranular layer (SGL) of the dentate gyrus express high levels of plasma membrane-bound nucleoside triphosphate diphosphohydrolase 2 (NTPDase2), an ectoenzyme that hydrolyzes extracellular nucleoside diphosphates and triphosphates. We inferred that deletion of NTPDase2 would increase local extracellular nucleoside triphosphate concentrations perturbing purinergic signaling and boosting progenitor cell proliferation and neurogenesis. Using newly generated mice globally null for Entpd2, we demonstrate that NTPDase2 is the major ectonucleotidase in these progenitor cell-rich areas. Using BrdU-labeling protocols, we have measured stem cell proliferation and determined long-term survival of cell progeny under basal conditions. Brains of Entpd2 null mice revealed increased progenitor cell proliferation in both the SVZ and the SGL. However, this occurred without noteworthy alterations in long-term progeny survival. The hippocampal stem cell pool and the pool of the intermediate progenitor type-2 cells clearly expanded. However, substantive proportions of these proliferating cells were lost during expansion at around type-3 stage. Cell loss was paralleled by decreases in cAMP response element-binding protein phosphorylation in the doublecortin-positive progenitor cell population and by an increase in labeling for activated caspase-3 levels. We propose that NTPDase2 has functionality in scavenging mitogenic extracellular nucleoside triphosphates in neurogenic niches of the adult brain, thereby acting as a homeostatic regulator of nucleotide-mediated neural progenitor cell proliferation and expansion.

  17. The role of DNA damage repair in aging of adult stem cells.

    PubMed

    Kenyon, Jonathan; Gerson, Stanton L

    2007-01-01

    DNA repair maintains genomic stability and the loss of DNA repair capacity results in genetic instability that may lead to a decline of cellular function. Adult stem cells are extremely important in the long-term maintenance of tissues throughout life. They regenerate and renew tissues in response to damage and replace senescent terminally differentiated cells that no longer function. Oxidative stress, toxic byproducts, reduced mitochondrial function and external exposures all damage DNA through base modification or mis-incorporation and result in DNA damage. As in most cells, this damage may limit the survival of the stem cell population affecting tissue regeneration and even longevity. This review examines the hypothesis that an age-related loss of DNA damage repair pathways poses a significant threat to stem cell survival and longevity. Normal stem cells appear to have strict control of gene expression and DNA replication whereas stem cells with loss of DNA repair may have altered patterns of proliferation, quiescence and differentiation. Furthermore, stem cells with loss of DNA repair may be susceptible to malignant transformation either directly or through the emergence of cancer-prone stem cells. Human diseases and animal models of loss of DNA repair provide longitudinal analysis of DNA repair processes in stem cell populations and may provide links to the physiology of aging.

  18. Isolation of multipotent neural stem/progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse

    PubMed Central

    Guo, Weixiang; Patzlaff, Natalie E.; Jobe, Emily M.; Zhao, Xinyu

    2013-01-01

    In adult mammals, the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone of the dentate gyrus (DG) demonstrate ongoing neurogenesis, and multipotent neural stem/progenitor cells (NSCs) in these two regions exhibit different intrinsic properties. However, investigation of the mechanisms underlying such differences has been limited by a lack of efficient methods for isolating NSCs, particularly from the adult DG. Here we describe a protocol that enables us to isolate self-renewing and multipotent NSCs from the SVZ and the DG of the same adult mouse. The protocol involves the microdissection of the SVZ and DG from one adult mouse brain, isolation of NSCs from specific regions, and cultivation of NSCs in vitro. The entire procedure takes 2 to 3 hours. Since only one mouse is needed for each cell isolation procedure, this protocol will be particularly useful for studies with limited availability of mice, such as mice that contain multiple genetic modifications. PMID:23080272

  19. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles.

    PubMed

    Lei, Lei; Spradling, Allan C

    2013-05-21

    Whether or not mammalian females generate new oocytes during adulthood from germ-line stem cells to sustain the ovarian follicle pool has recently generated controversy. We used a sensitive lineage-labeling system to determine whether stem cells are needed in female adult mice to compensate for follicular losses and to directly identify active germ-line stem cells. Primordial follicles generated during fetal life are highly stable, with a half-life during adulthood of 10 mo, and thus are sufficient to sustain adult oogenesis without a source of renewal. Moreover, in normal mice or following germ-cell depletion with Busulfan, only stable, single oocytes are lineage-labeled, rather than cell clusters indicative of new oocyte formation. Even one germ-line stem cell division per 2 wk would have been detected by our method, based on the kinetics of fetal follicle formation. Thus, adult female mice neither require nor contain active germ-line stem cells or produce new oocytes in vivo.

  20. Neural stem cells in the adult ciliary epithelium express GFAP and are regulated by Wnt signaling

    SciTech Connect

    Das, Ani V.; Zhao Xing; James, Jackson; Kim, Min; Cowan, Kenneth H.; Ahmad, Iqbal . E-mail: iahmad@unmc.edu

    2006-01-13

    The identification of neural stem cells with retinal potential in the ciliary epithelium (CE) of the adult mammals is of considerable interest because of their potential for replacing or rescuing degenerating retinal neurons in disease or injury. The evaluation of such a potential requires characterization of these cells with regard to their phenotypic properties, potential, and regulatory mechanisms. Here, we demonstrate that rat CE stem cells/progenitors in neurosphere culture display astrocytic nature in terms of expressing glial intermediate neurofilament protein, GFAP. The GFAP-expressing CE stem cells/progenitors form neurospheres in proliferating conditions and generate neurons when shifted to differentiating conditions. These cells express components of the canonical Wnt pathway and its activation promotes their proliferation. Furthermore, we demonstrate that the activation of the canonical Wnt pathway influences neuronal differentiation of CE stem cells/progenitors in a context dependent manner. Our observations suggest that CE stem cells/progenitors share phenotypic properties and regulatory mechanism(s) with neural stem cells elsewhere in the adult CNS.

  1. Identification of multipotent stem cells from adult dog periodontal ligament.

    PubMed

    Wang, Wen-Jun; Zhao, Yu-Ming; Lin, Bi-Chen; Yang, Jie; Ge, Li-Hong

    2012-08-01

    Periodontal diseases, which are characterized by destruction of the connective tissues responsible for restraining the teeth within the jaw, are the main cause of tooth loss. Periodontal regeneration mediated by human periodontal ligament stem cells (hPDLSCs) may offer an alternative strategy for the treatment of periodontal disease. Dogs are a widely used large-animal model for the study of periodontal-disease progression, tissue regeneration, and dental implants, but little attention has been paid to the identification of the cells involved in this species. This study aimed to characterize stem cells isolated from canine periodontal ligament (cPDLSCs). The cPDLSCs, like hPDLSCs, showed clonogenic capability and expressed the mesenchymal stem cell markers STRO-1, CD146, and CD105, but not CD34. After induction of osteogenesis, cPDLSCs showed calcium accumulation in vitro. Moreover, cPDLSCs also showed both adipogenic and chondrogenic potential. Compared with cell-free controls, more cementum/periodontal ligament-like structures were observed in CB-17/SCID mice into which cPDLSCs had been transplanted. These results suggest that cPDLSCs are clonogenic, highly proliferative, and have multidifferentiation potential, and that they could be used as a new cellular therapeutic approach to facilitate successful and more predictable regeneration of periodontal tissue using a canine model of periodontal disease.

  2. Mesenchymal stem cells from the outer ear: a novel adult stem cell model system for the study of adipogenesis.

    PubMed

    Rim, Jong-Seop; Mynatt, Randall L; Gawronska-Kozak, Barbara

    2005-07-01

    Adipocytes arise from multipotent stem cells of mesodermal origin, which also give rise to the muscle, bone, and cartilage lineages. However, signals and early molecular events that commit multipotent stem cells into the adipocyte lineage are not well established mainly due to lack of an adequate model system. We have identified a novel source of adult stem cells from the external murine ears referred to here as an ear mesenchymal stem cells (EMSC). EMSC have been isolated from several standard and mutant strains of mice. They are self-renewing, clonogenic, and multipotent, since they give rise to osteocytes, chondrocytes, and adipocytes. The in vitro characterization of EMSC indicates very facile adipogenic differentiation. Morphological, histochemical, and molecular analysis after the induction of differentiation showed that EMSC maintain adipogenic potentials up to fifth passage. A comparison of EMSC to the stromal-vascular (S-V) fraction of fat depots, under identical culture conditions (isobutyl-methylxanthine, dexamethasone, and insulin), revealed much more robust and consistent adipogenesis in EMSC than in the S-V fraction. In summary, we show that EMSC can provide a novel, easily obtainable, primary culture model for the study of adipogenesis.

  3. [Intraoperative neurophysiological monitoring of brain stem in a case of cavernoma in the pons].

    PubMed

    Rodríguez, R; Molet, J; de Teresa, S; Treserras, P; Clavel, P; Cano, P; Solivera, J; Muñoz, F; Bartumeus, F

    2005-04-01

    Neurophysiological monitoring during surgery to avoid damaging of eloquent brain areas is a useful tool. We are performing intraoperative neurophysiological test to locate motor, sensitive and speech areas with cortical stimulation and cranial nerves during cerebellopontine cranial base surgery. Neurophysiological monitoring during brain stem surgery has been less described. Brain stem surgery implies a careful selection of patients for surgery given the high risk of morbidity and mortality. For this reason, conservative treatment is usually indicated when an asymptomatic cavernoma is incidentally found. Instead, when bleeding or neurological deficit appear, operative treatment may be indicated and then the goal of surgery is to avoid the disability linked to the natural history. We present the case of a 29 year old woman with diagnosis of multiple cavernomas. She was admitted at our hospital because she presented weakness and sensitive disturbance of left limbs and dizziness. The CT scan and MRI showed a pontine haemorrhage caused by a cavernous hemangioma. We operated her on using neurophysiological monitoring of VII, VIII, X and XII cranial nerves with electromyographic recordings. Postoperative disability could be reduced with a better knowledge of entry zone into the brain stem and early physiotherapy.

  4. Genomic selection for quantitative adult plant stem rust resistance in wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Quantitative adult plant resistance (APR) to stem rust (Puccinia graminis f. sp. tritici) is an important breeding target in wheat (Triticum aestivum L.) and a potential target for genomic selection (GS). To evaluate the relative importance of known APR loci in applying genomic selection, we charact...

  5. zebraflash transgenic lines for in vivo bioluminescence imaging of stem cells and regeneration in adult zebrafish.

    PubMed

    Chen, Chen-Hui; Durand, Ellen; Wang, Jinhu; Zon, Leonard I; Poss, Kenneth D

    2013-12-01

    The zebrafish has become a standard model system for stem cell and tissue regeneration research, based on powerful genetics, high tissue regenerative capacity and low maintenance costs. Yet, these studies can be challenged by current limitations of tissue visualization techniques in adult animals. Here we describe new imaging methodology and present several ubiquitous and tissue-specific luciferase-based transgenic lines, which we have termed zebraflash, that facilitate the assessment of regeneration and engraftment in freely moving adult zebrafish. We show that luciferase-based live imaging reliably estimates muscle quantity in an internal organ, the heart, and can longitudinally follow cardiac regeneration in individual animals after major injury. Furthermore, luciferase-based detection enables visualization and quantification of engraftment in live recipients of transplanted hematopoietic stem cell progeny, with advantages in sensitivity and gross spatial resolution over fluorescence detection. Our findings present a versatile resource for monitoring and dissecting vertebrate stem cell and regeneration biology.

  6. Strategies to enhance umbilical cord blood stem cell engraftment in adult patients

    PubMed Central

    Delaney, Colleen; Ratajczak, Mariusz Z; Laughlin, Mary J

    2010-01-01

    Umbilical cord blood (UCB) has been used successfully as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation in children and adults in the treatment of hematologic diseases. However, compared with marrow or mobilized peripheral blood stem cell grafts from adult donors, significant delays in the rates and kinetics of neutrophil and platelet engraftment are noted after UCB transplant. These differences relate in part to the reduced numbers of HSCs in UCB grafts. To improve the rates and kinetics of engraftment of UCB HSC, several strategies have been proposed, including ex vivo expansion of UCB HSCs, addition of third-party mesenchymal cells, intrabone delivery of HSCs, modulation of CD26 expression, and infusion of two UCB grafts. This article will focus on ex vivo expansion of UCB HSCs and strategies to enhance UCB homing as potential solutions to overcome the problem of low stem cell numbers in a UCB graft. PMID:20835351

  7. Cell-permeable p38 MAP kinase promotes migration of adult neural stem/progenitor cells

    PubMed Central

    Hamanoue, Makoto; Morioka, Kazuhito; Ohsawa, Ikuroh; Ohsawa, Keiko; Kobayashi, Masaaki; Tsuburaya, Kayo; Akasaka, Yoshikiyo; Mikami, Tetsuo; Ogata, Toru; Takamatsu, Ken

    2016-01-01

    Endogenous neural stem/progenitor cells (NPCs) can migrate toward sites of injury, but the migration activity of NPCs is insufficient to regenerate damaged brain tissue. In this study, we showed that p38 MAP kinase (p38) is expressed in doublecortin-positive adult NPCs. Experiments using the p38 inhibitor SB203580 revealed that endogenous p38 participates in NPC migration. To enhance NPC migration, we generated a cell-permeable wild-type p38 protein (PTD-p38WT) in which the HIV protein transduction domain (PTD) was fused to the N-terminus of p38. Treatment with PTD-p38WT significantly promoted the random migration of adult NPCs without affecting cell survival or differentiation; this effect depended on the cell permeability and kinase activity of the fusion protein. These findings indicate that PTD-p38WT is a novel and useful tool for unraveling the roles of p38, and that this protein provides a reasonable approach for regenerating the injured brain by enhancing NPC migration. PMID:27067799

  8. cGMP modulates stem cells differentiation to neurons in brain in vivo.

    PubMed

    Gómez-Pinedo, U; Rodrigo, R; Cauli, O; Herraiz, S; Garcia-Verdugo, J-M; Pellicer, B; Pellicer, A; Felipo, V

    2010-02-17

    During brain development neural stem cells may differentiate to neurons or to other cell types. The aim of this work was to assess the role of cGMP (cyclic GMP) in the modulation of differentiation of neural stem cells to neurons or non-neuronal cells. cGMP in brain of fetuses was reduced to 46% of controls by treating pregnant rats with nitroarginine-methylester (L-NAME) and was restored by co-treatment with sildenafil.Reducing cGMP during brain development leads to reduced differentiation of stem cells to neurons and increased differentiation to non-neuronal cells. The number of neurons in the prefrontal cortex originated from stem cells proliferating on gestational day 14 was 715+/-14/mm(2) in control rats and was reduced to 440+/-29/mm(2) (61% of control) in rats treated with L-NAME. In rats exposed to L-NAME plus sildenafil, differentiation to neurons was completely normalized, reaching 683+/-11 neurons/mm(2). In rats exposed to sildenafil alone the number of cells labelled with bromodeoxyuridine (BrdU) and NeuN was 841+/-16/mm(2). In prefrontal cortex of control rats 48% of the neural stem cells proliferating in gestational day 14 differentiate to neurons, but only 24% in rats exposed to L-NAME. This was corrected by sildenafil, 40% of cells differentiate to neurons. Similar results were obtained for neurons proliferating during all developmental period. Treatment with L-NAME did not reduce the total number of cells labelled with BrdU, further supporting that L-NAME reduces selectively the differentiation of stem cells to neurons. Similar results were obtained in hippocampus. Treatment with L-NAME reduced the differentiation of neural stem cells to neurons, although the effect was milder than in prefrontal cortex. These results support that cGMP modulates the fate of neural stem cells in brain in vivo and suggest that high cGMP levels promote its differentiation to neurons while reduced cGMP levels promote differentiation to non-neuronal cells.

  9. Neurogenesis in the brain stem of the rabbit: an autoradiographic study

    SciTech Connect

    Oblinger, M.M.; Das, G.D.

    1981-03-20

    With the aid of (/sup 3/H)-thymidine autoradiography, neurogenesis was documented in the nuclear groups of the medulla oblongata, pons, and mid-brain, as well as in the brain stem reticular formation of the rabbit. Following single injections of (/sup 3/H)-thymidine, counts were taken of intensely labeled neurons within the nuclei of the functional columns related to the cranial nerves, nuclei of several other functional classifications, and nuclei that did not fit into a functional category. In the brain stem as a whole, neurogenesis was found to occur between days 10.0 and 18.5 of gestation: however, the majority of nuclei studied contained intensely neurons only between days 12.0 and 15.0. Only in the pontine nucleus and the tectum were intensely labeled cells observed as late as day 18.5. Directional gradients of histogenesis were often observed within, as well as between, various nuclei. Within the nuclear columns related to the cranial nerves, a clear mediolateral spread of neurogenesis was observable such that nuclei of the motor columns reached a peak in neurogenesis before those in the sensory columns. Likewise, a mediolateral proliferation pattern was seen in the brain stem reticular formation. Other individual directional gradients were discernible; however, in the brain stem as a whole, distinct overall gradients were not observable. In many individual nuclei, gradients in neuron size were observed such that large neurons preferentially arose prior to smaller neurons. Information pertaining to gradients in neurogenesis, as well as to relationships among functionally related nuclei, are discussed.

  10. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.

    PubMed

    Kilcoyne, Karen R; Smith, Lee B; Atanassova, Nina; Macpherson, Sheila; McKinnell, Chris; van den Driesche, Sander; Jobling, Matthew S; Chambers, Thomas J G; De Gendt, Karel; Verhoeven, Guido; O'Hara, Laura; Platts, Sophie; Renato de Franca, Luiz; Lara, Nathália L M; Anderson, Richard A; Sharpe, Richard M

    2014-05-06

    Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.

  11. Stroke Increases Neural Stem Cells and Angiogenesis in the Neurogenic Niche of the Adult Mouse

    PubMed Central

    Zhang, Rui Lan; Chopp, Michael; Roberts, Cynthia; Liu, Xianshuang; Wei, Min; Nejad-Davarani, Siamak P.; Wang, Xinli; Zhang, Zheng Gang

    2014-01-01

    The unique cellular and vascular architecture of the adult ventricular-subventricular zone (V/SVZ) neurogenic niche plays an important role in regulating neural stem cell function. However, the in vivo identification of neural stem cells and their relationship to blood vessels within this niche in response to stroke remain largely unknown. Using whole-mount preparation of the lateral ventricle wall, we examined the architecture of neural stem cells and blood vessels in the V/SVZ of adult mouse over the course of 3 months after onset of focal cerebral ischemia. Stroke substantially increased the number of glial fibrillary acidic protein (GFAP) positive neural stem cells that are in contact with the cerebrospinal fluid (CSF) via their apical processes at the center of pinwheel structures formed by ependymal cells residing in the lateral ventricle. Long basal processes of these cells extended to blood vessels beneath the ependymal layer. Moreover, stroke increased V/SVZ endothelial cell proliferation from 2% in non-ischemic mice to 12 and 15% at 7 and 14 days after stroke, respectively. Vascular volume in the V/SVZ was augmented from 3% of the total volume prior to stroke to 6% at 90 days after stroke. Stroke-increased angiogenesis was closely associated with neuroblasts that expanded to nearly encompass the entire lateral ventricular wall in the V/SVZ. These data indicate that stroke induces long-term alterations of the neural stem cell and vascular architecture of the adult V/SVZ neurogenic niche. These post-stroke structural changes may provide insight into neural stem cell mediation of stroke-induced neurogenesis through the interaction of neural stem cells with proteins in the CSF and their sub-ependymal neurovascular interaction. PMID:25437857

  12. Bone marrow-derived mesenchymal stem cells differentiate into nerve-like cells in vitro after transfection with brain-derived neurotrophic factor gene.

    PubMed

    Liu, Qianxu; Cheng, Guangui; Wang, Zhiwei; Zhan, Shujie; Xiong, Binbin; Zhao, Xiaoming

    2015-03-01

    Bone marrow-derived mesenchymal stem cells can differentiate into a variety of adult cells. Brain-derived neurotrophic factor (BDNF) is briefly active during differentiation and induces mesenchymal stem cells to differentiate into nerve cells. In this study, we cloned human BDNF to generate a recombinant pcDNA3.1(-)-BDNF vector and transfected the vector into bone marrow-derived mesenchymal stem cells. We selected these cells with Geneticin-418 to obtain BDNF-BMSCs, which were induced with retinoic acid to obtain induced BDNF-BMSCs. The transfected cells displayed the typical morphology and surface antigen profile of fibroblasts and were observed to express clusters of differentiation 29, 44, and 90 (observed in matrix and stromal cells), but not clusters of differentiation 31, 34, and 45 (observed in red blood cells and endothelial cells), via flow cytometry. Enzyme-linked immunosorbent assays showed that transfected bone marrow-derived mesenchymal stem cells secreted more BDNF than non-transfected bone marrow-derived mesenchymal stem cells. Immunocytochemistry and real-time reverse transcription polymerase chain reaction analysis showed that non-induced BDNF-BMSCs maintained a higher proliferative capacity and expressed higher amounts of brain-derived neurotrophic factor, nestin, neuron-specific enolase, and glial fibrillary acid protein than non-transfected bone marrow-derived mesenchymal stem cells. An additional increase was observed in the induced BDNF-BMSCs compared to the non-induced BDNF-BMSCs. This expression profile is characteristic of neurocytes. Our data demonstrate that bone marrow-derived mesenchymal stem cells transfected with the BDNF gene can differentiate into nerve-like cells in vitro, which may enable the generation of sufficient quantities of nerve-like cells for treatment of neuronal diseases.

  13. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells.

    PubMed

    Lippmann, Ethan S; Azarin, Samira M; Kay, Jennifer E; Nessler, Randy A; Wilson, Hannah K; Al-Ahmad, Abraham; Palecek, Sean P; Shusta, Eric V

    2012-08-01

    The blood-brain barrier (BBB) is crucial to the health of the brain and is often compromised in neurological disease. Moreover, because of its barrier properties, this endothelial interface restricts uptake of neurotherapeutics. Thus, a renewable source of human BBB endothelium could spur brain research and pharmaceutical development. Here we show that endothelial cells derived from human pluripotent stem cells (hPSCs) acquire BBB properties when co-differentiated with neural cells that provide relevant cues, including those involved in Wnt/β-catenin signaling. The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 ± 140 Ω cm2), and they possess molecular permeability that correlates well with in vivo rodent blood-brain transfer coefficients.

  14. 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.

  15. How electromagnetic fields can influence adult stem cells: positive and negative impacts.

    PubMed

    Maziarz, Aleksandra; Kocan, Beata; Bester, Mariusz; Budzik, Sylwia; Cholewa, Marian; Ochiya, Takahiro; Banas, Agnieszka

    2016-04-18

    The electromagnetic field (EMF) has a great impact on our body. It has been successfully used in physiotherapy for the treatment of bone disorders and osteoarthritis, as well as for cartilage regeneration or pain reduction. Recently, EMFs have also been applied in in vitro experiments on cell/stem cell cultures. Stem cells reside in almost all tissues within the human body, where they exhibit various potential. These cells are of great importance because they control homeostasis, regeneration, and healing. Nevertheless, stem cells when become cancer stem cells, may influence the pathological condition. In this article we review the current knowledge on the effects of EMFs on human adult stem cell biology, such as proliferation, the cell cycle, or differentiation. We present the characteristics of the EMFs used in miscellaneous assays. Most research has so far been performed during osteogenic and chondrogenic differentiation of mesenchymal stem cells. It has been demonstrated that the effects of EMF stimulation depend on the intensity and frequency of the EMF and the time of exposure to it. However, other factors may affect these processes, such as growth factors, reactive oxygen species, and so forth. Exploration of this research area may enhance the development of EMF-based technologies used in medical applications and thereby improve stem cell-based therapy and tissue engineering.

  16. A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues

    PubMed Central

    Simerman, Ariel A; Perone, Marcelo J; Gimeno, María L; Dumesic, Daniel A; Chazenbalk, Gregorio D

    2014-01-01

    Introduction: Embryonic stem cells and induced pluripotent stem cells have emerged as the gold standard of pluripotent stem cells and the class of stem cell with the highest potential for contribution to regenerative and therapeutic application; however, their translational use is often impeded by teratoma formation, commonly associated with pluripotency. We discuss a population of nontumorigenic pluripotent stem cells, termed Multilineage Differentiating Stress Enduring (Muse) cells, which offer an innovative and exciting avenue of exploration for the potential treatment of various human diseases. Areas covered: This review discusses the origin of Muse cells, describes in detail their various unique characteristics, and considers future avenues of their application and investigation with respect to what is currently known of adult pluripotent stem cells in scientific literature. We begin by defining cell potency, then discuss both mesenchymal and various reported populations of pluripotent stem cells, and finally delve into Muse cells and the characteristics that set them apart from their contemporaries. Expert opinion: Muse cells derived from adipose tissue (Muse-AT) are efficiently, routinely and painlessly isolated from human lipoaspirate material, exhibit tripoblastic differentiation both spontaneously and under media-specific induction, and do not form teratomas. We describe qualities specific to Muse-AT cells and their potential impact on the field of regenerative medicine and cell therapy. PMID:24745973

  17. Isolating intestinal stem cells from adult Drosophila midguts by FACS to study stem cell behavior during aging.

    PubMed

    Tauc, Helen M; Tasdogan, Alpaslan; Pandur, Petra

    2014-12-16

    Aging tissue is characterized by a continuous decline in functional ability. Adult stem cells are crucial in maintaining tissue homeostasis particularly in tissues that have a high turnover rate such as the intestinal epithelium. However, adult stem cells are also subject to aging processes and the concomitant decline in function. The Drosophila midgut has emerged as an ideal model system to study molecular mechanisms that interfere with the intestinal stem cells' (ISCs) ability to function in tissue homeostasis. Although adult ISCs can be easily identified and isolated from midguts of young flies, it has been a major challenge to study endogenous molecular changes of ISCs during aging. This is due to the lack of a combination of molecular markers suitable to isolate ISCs from aged intestines. Here we propose a method that allows for successful dissociation of midgut tissue into living cells that can subsequently be separated into distinct populations by FACS. By using dissociated cells from the esg-Gal4, UAS-GFP fly line, in which both ISCs and the enteroblast (EB) progenitor cells express GFP, two populations of cells are distinguished based on different GFP intensities. These differences in GFP expression correlate with differences in cell size and granularity and represent enriched populations of ISCs and EBs. Intriguingly, the two GFP-positive cell populations remain distinctly separated during aging, presenting a novel technique for identifying and isolating cell populations enriched for either ISCs or EBs at any time point during aging. The further analysis, for example transcriptome analysis, of these particular cell populations at various time points during aging is now possible and this will facilitate the examination of endogenous molecular changes that occur in these cells during aging.

  18. Apple ethanol extract promotes proliferation of human adult stem cells, which involves the regenerative potential of stem cells.

    PubMed

    Lee, Jienny; Shin, Moon Sam; Kim, Mi Ok; Jang, Sunghee; Oh, Sae Woong; Kang, Mingyeong; Jung, Kwangseon; Park, Yong Seek; Lee, Jongsung

    2016-09-01

    Tissue regeneration using adult stem cells (ASCs) has significant potential as a novel treatment for many degenerative diseases. Previous studies have established that age negatively affects the proliferation status and differentiation potential of ASCs, suggesting a possible limitation in their potential therapeutic use. Therefore, we hypothesized that apple extract might exert beneficial effects on ASCs. The specific objectives were to investigate the proliferative effect of apple ethanol extract on human adipose tissue-derived mesenchymal stem cells (ADSCs) and human cord blood-derived mesenchymal stem cells (CB-MSCs), and identify the possible molecular mechanisms. Apple extract promoted proliferation of ADSCs and CB-MSCs as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Click-iT 5-ethynyl-2'-deoxyuridine flow cytometry assays. In addition, phosphorylation of p44/42 MAPK (ERK), mammalian target of rapamycin (mTOR), p70 S6 kinase (p70S6K), S6 ribosomal protein (S6RP), eukaryotic initiation factor (eIF) 4B and eIF4E was induced stepwise in ADSCs. Furthermore, apple extract significantly induced the production of vascular endothelial growth factor and interleukin-6 in both ADSCs and CB-MSCs. Similarly, apple extract-induced phosphorylation of the mTOR/p70S6K/S6RP/eIF4B/eIF4E pathway was blocked by pretreatment with PD98059, a specific ERK inhibitor. These results indicate that apple extract-induced proliferation of ADSCs under serum-free conditions is mediated by ERK-dependent cytokine production. Moreover, the beneficial effect of apple extract on proliferation of ASCs may overcome the limitation in therapeutic use of stem cells in tissue regeneration and maintenance of stem cell homeostasis.

  19. Effect of acupuncture on the auditory evoked brain stem potential in Parkinson's disease.

    PubMed

    Wang, Lingling; He, Chong; Liu, Yueguang; Zhu, Lili

    2002-03-01

    Under the auditory evoked brain stem potential (ABP) examination, the latent period of V wave and the intermittent periods of III-V peak and I-V peak were significantly shortened in Parkinson's disease patients of the treatment group (N = 29) after acupuncture treatment. The difference of cumulative scores in Webster's scale was also decreased in correlation analysis. The increase of dopamine in the brain and the excitability of the dopamine neurons may contribute to the therapeutic effects, in TCM terms, of subduing the pathogenic wind and tranquilizing the mind.

  20. Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu

    PubMed Central

    Mansouri, Shiva; Lietzau, Grazyna; Lundberg, Mathias; Nathanson, David; Nyström, Thomas; Patrone, Cesare

    2016-01-01

    Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia. PMID:27305000

  1. A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues.

    PubMed

    Ratajczak, M Z; Machalinski, B; Wojakowski, W; Ratajczak, J; Kucia, M

    2007-05-01

    Accumulating evidence demonstrates that adult tissues contain a population of stem cells that express early developmental markers such as stage-specific embryonic antigen and transcription factors Oct-4 and Nanog. These are the markers characteristic for embryonic stem cells, epiblast stem cells and primordial germ cells. The presence of these stem cells in adult tissues including bone marrow, epidermis, bronchial epithelium, myocardium, pancreas and testes supports the concept that adult tissues contain some population of pluripotent stem cells that is deposited in embryogenesis during early gastrulation. In this review we will discuss these data and present a hypothesis that these cells could be direct descendants of the germ lineage. The germ lineage in order to pass genes on to the next generations creates soma and thus becomes a 'mother lineage' for all somatic cell lineages present in the adult body.

  2. Enhanced brain stem 5HT₂A receptor function under neonatal hypoxic insult: role of glucose, oxygen, and epinephrine resuscitation.

    PubMed

    Anju, T R; Korah, P K; Jayanarayanan, S; Paulose, C S

    2011-08-01

    Molecular processes regulating brain stem serotonergic receptors play an important role in the control of respiration. We evaluated 5-HT(2A) receptor alterations in the brain stem of neonatal rats exposed to hypoxic insult and the effect of glucose, oxygen, and epinephrine resuscitation in ameliorating these alterations. Hypoxic stress increased the total 5-HT and 5-HT(2A) receptor number along with an up regulation of 5-HT Transporter and 5-HT(2A) receptor gene in the brain stem of neonates. These serotonergic alterations were reversed by glucose supplementation alone and along with oxygen to hypoxic neonates. The enhanced brain stem 5-HT(2A) receptors act as a modulator of ventilatory response to hypoxia, which can in turn result in pulmonary vasoconstriction and cognitive dysfunction. The adverse effects of 100% oxygenation and epinephrine administration to hypoxic neonates were also reported. This has immense clinical significance in neonatal care.

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

    PubMed Central

    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. PMID:25143726

  4. Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals

    PubMed Central

    Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth; Miller, Elaine; Ariza, Jeanelle; Kienzle, Devon; Plank, Kaela; Noctor, Stephen C.; Van de Water, Judy

    2016-01-01

    Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased stem cell proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor. PMID:25535268

  5. S100A6 (calcyclin) is a novel marker of neural stem cells and astrocyte precursors in the subgranular zone of the adult mouse hippocampus.

    PubMed

    Yamada, Jun; Jinno, Shozo

    2014-01-01

    S100A6 (calcyclin), an EF-hand calcium binding protein, is considered to play various roles in the brain, for example, cell proliferation and differentiation, calcium homeostasis, and neuronal degeneration. In addition to some limbic nuclei, S100A6 is distributed in the rostral migratory stream, one of the major neurogenic niches of the adult brain. However, the potential involvement of S100A6 in adult neurogenesis remains unclear. In this study, we aimed to elucidate the role of S100A6 in the other major neurogenic niche, the subgranular zone of the dentate gyrus in the adult mouse hippocampus. Immunofluorescent multiple labeling showed that S100A6 was highly expressed in neural stem cells labeled by sex determining region Y-box 2, brain lipid-binding protein protein and glial fibrillary acidic protein. S100A6+ cells often extended a long process typical of radial glial morphology. In addition, S100A6 was found in some S100β+ astrocyte lineage cells. Interestingly, proliferating cell nuclear antigen was detected in a fraction of S100A6+/S100β+ cells. These cells were considered to be lineage-restricted astrocyte precursors maintaining mitotic potential. On the other hand, S100A6 was rarely seen in neural lineage cells labeled by T-box brain protein 2, doublecortin, calretinin and calbindin D28K. Cell fate-tracing experiment using BrdU showed that the majority of newly generated immature astrocytes were immunoreactive for S100A6, while mature astrocytes lacked S100A6 immunoreactivity. Administration of S100 protein inhibitor, trifluoperazine, caused a reduction in production of S100β+ astrocyte lineage cells, but had no impact on neurogenesis. Overall, our data provide the first evidence that S100A6 is a specific marker of neural stem cells and astrocyte precursors, and may be especially important for generation of astrocytes in the adult hippocampus.

  6. A Comprehensive Study of the Anatomical Variations of the Circle of Willis in Adult Human Brains

    PubMed Central

    Iqbal, S.

    2013-01-01

    Background: Cerebrovascular diseases such as stroke, aneurysms and arterio-venous malformations are very much prevalent in our country. Circle of Willis, as an anastomotic polygon at the base of the brain forms an important collateral network to maintain adequate cerebral perfusion. Changes in the normal morphology of the circle may condition the appearance and severity of symptoms of cerebrovascular disorders, such as aneurysms, infarctions and other vascular anomalies. A possible link between abnormalities of the circle of Willis and the mentally ill patients has been observed. Aim and Objectives: The aim of the present study is to have an intimate knowledge of the variations in the cerebral arterial circle and to clarify the clinical importance of these variations in certain forms of cerebrovascular diseases. So an attempt was made to analyse the anatomical variations of the circle in a random population. Material and Methods: The work was based on fifty adult brains from persons died of diverse causes. The materials were obtained during routine autopsy studies. The base of the brain including the brain stem with intact arterial circle was preserved in 10% formalin for 10 days. The circle of Willis and its major branches were carefully dissected under water using a magnifying lens. The variations were recorded and photographed. Results: Majority of the circles (52%) showed anomalies. Hypoplasia was the most frequent anomaly and was found in 24% of the brains. Accessory vessels in the form of duplications/triplications of anterior communicating artery were seen in 12% of the circles. The embryonic origin of the posterior cerebral artery from the internal carotid persisted in 10% of the circles. An incomplete circle due to the absence of one or other posterior communicating artery was found in 6% of the specimens.Variations are more frequent in posterior half of the circle. Conclusion: The anatomical variations of the circle of Willis were probably genetically

  7. [Trismus, trigeminal motor dyssynergy with brain stem lesions (author's transl)].

    PubMed

    Jelasic, F; Freitag, V

    1975-08-01

    Paradox activity of masticatory muscles was observed clinically and electromyographically in 4 patients with brain steem lesions who had trismus. There was no activity in the elevators of the jaw on the side affected during voluntary biting, as if the muscles were paralyzed. There was strong activity of the elevators on the side of the trismus on opening the mouth, inactivity on the unaffected side, or inverse activity appeared on both sides. In view of the trigeminal anesthesia on the side of paradox activation, and the absence of pyramidal signs, a stretch reflex mechanism and abolition of inhibition can not be the only basis for these phenomena; so, a disturbance of bilateral synergism, in the sense of an internuclear lesion, is postulated. In one case of motor and sensory paralysis after the extirpation of a meningioma of the cerebellopontine angle, intensive paradox activity was observed, without trismus.

  8. Micropatterning control of tubular commitment in human adult renal stem cells.

    PubMed

    Sciancalepore, Anna G; Portone, Alberto; Moffa, Maria; Persano, Luana; De Luca, Maria; Paiano, Aurora; Sallustio, Fabio; Schena, Francesco P; Bucci, Cecilia; Pisignano, Dario

    2016-07-01

    The treatment of renal injury by autologous, patient-specific adult stem cells is still an unmet need. Unsolved issues remain the spatial integration of stem cells into damaged areas of the organ, the commitment in the required cell type and the development of improved bioengineered devices. In this respect, biomaterials and architectures have to be specialized to control stem cell differentiation. Here, we perform an extensive study on micropatterned extracellular matrix proteins, which constitute a simple and non-invasive approach to drive the differentiation of adult renal progenitor/stem cells (ARPCs) from human donors. ARPCs are interfaced with fibronectin (FN) micropatterns, in the absence of exogenous chemicals or cellular reprogramming. We obtain the differentiation towards tubular cells of ARPCs cultured in basal medium conditions, the tubular commitment thus being specifically induced by micropatterned substrates. We characterize the stability of the tubular differentiation as well as the induction of a polarized phenotype in micropatterned ARPCs. Thus, the developed cues, driving the functional commitment of ARPCs, offer a route to recreate the microenvironment of the stem cell niche in vitro, that may serve, in perspective, for the development of ARPC-based bioengineered devices.

  9. Comparative analysis of mesenchymal stem cells from adult mouse adipose, muscle, and fetal muscle.

    PubMed

    Lei, Hulong; Yu, Bing; Huang, Zhiqing; Yang, Xuerong; Liu, Zehui; Mao, Xiangbing; Tian, Gang; He, Jun; Han, Guoquan; Chen, Hong; Mao, Qian; Chen, Daiwen

    2013-02-01

    Recently, increasing evidence supports that adult stem cells are the part of a natural system for tissue growth and repair. This study focused on the differences of mesenchymal stem cells from adult adipose (ADSCs), skeletal muscle (MDSCs) and fetal muscle (FMSCs) in biological characteristics, which is the key to cell therapy success. Stem cell antigen 1 (Sca-1) expression of MDSCs and FMSCs at passage 3 was two times more than that at passage 1 (P < 0.0001). After 28-day myogenic induction, higher expression levels of skeletal muscle-specific genes were observed in MDSCs than FMSCs (P < 0.01), and the lowest expression levels were demonstrated in ADSCs among three cells (P < 0.01). Besides, M-Cad and MyHC expressions in ADSCs were not detected by immunofluorescence or real-time quantitative PCR. Furthermore, after 14 days adipogenic induction, PPARγ2, LPL and aP2 mRNA expressions were higher in ADSCs vs. MDSCs (P < 0.01). Besides, MSCs from adult or fetal muscle expressed higher OCN and OPN than ADSCs after 28 days osteogenic induction (P < 0.01). Taken together, our results suggested that cell source and developmental stage had great impacts on biological properties of mesenchymal stem cells, and proper consideration of all the issues is necessary.

  10. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation.

    PubMed

    Foronda, Miguel; Morgado-Palacin, Lucia; Gómez-López, Gonzalo; Domínguez, Orlando; Pisano, David G; Blasco, Maria A

    2015-12-01

    Adult stem cells (ASCs) reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014). Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013). Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4 (cKO) mice), we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC) activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4 (cKO) mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014). Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  11. Differentiation and characteristics of undifferentiated mesenchymal stem cells originating from adult premolar periodontal ligaments

    PubMed Central

    Kwon, Dae-Woo; Im, Insook; Kim, Yong-Deok; Hwang, Dae-Seok; Holliday, L Shannon; Donatelli, Richard E; Son, Woo-Sung; Jun, Eun-Sook

    2012-01-01

    Objective The purpose of this study was to investigate the isolation and characterization of multipotent human periodontal ligament (PDL) stem cells and to assess their ability to differentiate into bone, cartilage, and adipose tissue. Methods PDL stem cells were isolated from 7 extracted human premolar teeth. Human PDL cells were expanded in culture, stained using anti-CD29, -CD34, -CD44, and -STRO-1 antibodies, and sorted by fluorescent activated cell sorting (FACS). Gingival fibroblasts (GFs) served as a positive control. PDL stem cells and GFs were cultured using standard conditions conducive for osteogenic, chondrogenic, or adipogenic differentiation. Results An average of 152.8 ± 27.6 colony-forming units was present at day 7 in cultures of PDL stem cells. At day 4, PDL stem cells exhibited a significant increase in proliferation (p < 0.05), reaching nearly double the proliferation rate of GFs. About 5.6 ± 4.5% of cells in human PDL tissues were strongly STRO-1-positive. In osteogenic cultures, calcium nodules were observed by day 21 in PDL stem cells, which showed more intense calcium staining than GF cultures. In adipogenic cultures, both cell populations showed positive Oil Red O staining by day 21. Additionally, in chondrogenic cultures, PDL stem cells expressed collagen type II by day 21. Conclusions The PDL contains multipotent stem cells that have the potential to differentiate into osteoblasts, chondrocytes, and adipocytes. This adult PDL stem cell population can be utilized as potential sources of PDL in tissue engineering applications. PMID:23323245

  12. VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

    SciTech Connect

    Sun, Jinqiao; Sha, Bin; Zhou, Wenhao; Yang, Yi

    2010-03-26

    This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

  13. Human neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases.

    PubMed

    Joo, Kyeung Min; Park, In H; Shin, Ji Y; Jin, Juyoun; Kang, Bong Gu; Kim, Mi Hyun; Lee, Se Jeong; Jo, Mi-young; Kim, Seung U; Nam, Do-Hyun

    2009-03-01

    The tumor-tropic properties of neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to tumors in the brain. To apply this strategy to the treatment of brain metastases, we made a human NSC line expressing cytosine deaminase (F3.CD), which converts 5-fluorocytosine (5-FC) into 5-fluorouracil, an anticancer agent. In vitro, the F3.CD cells significantly inhibited the growth of tumor cell lines in the presence of the prodrug 5-FC. In vivo, MDA-MB-435 human breast cancer cells were implanted into the brain of immune-deficient mouse stereotactically, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. The F3.CD cells migrated selectively into the brain metastases located in the opposite hemisphere and resulted in significantly reduced volumes. The F3.CD and 5-FC treatment also decreased both tumor volume and number of tumor mass significantly, when immune-deficient mouse had MDA-MB-435 cells injected into the internal carotid artery and F3.CD cells were transplanted into the contralateral brain hemisphere stereotactically. Taken together, brain transplantation of human NSCs, encoding the suicide enzyme CD, combined with systemic administration of the prodrug 5-FC, is an effective treatment regimen for brain metastases of tumors.

  14. Inflammatory cues acting on the adult intestinal stem cells and the early onset of cancer (Review)

    PubMed Central

    DE LERMA BARBARO, A.; PERLETTI, G.; BONAPACE, I.M.; MONTI, E.

    2014-01-01

    The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcinogenesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initiation, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifically, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at ‘hijacking’ the crypt stem cell niche from a status characterized by the maintenance of homeostasis to local chronic inflammation, with the prospect of initiating

  15. Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges.

    PubMed

    Mitsialis, S Alex; Kourembanas, Stella

    2016-04-01

    There have been substantial advances in neonatal medical care over the past 2 decades that have resulted in the increased survival of very low birth weight infants, survival that in some centers extends to 22 weeks gestational age. Despite these advances, there continues to be significant morbidity associated with extreme preterm birth that includes both short-term and long-term pulmonary and neurologic consequences. No single therapy has proven to be effective in preventing or treating either developmental lung and brain injuries in preterm infants or the hypoxic-ischemic injury that can be inflicted on the full-term brain as a result of in utero or perinatal complications. Stem cell-based therapies are emerging as a potential paradigm-shifting approach for such complex diseases with multifactorial etiologies, but a great deal of work is still required to understand the role of stem/progenitor cells in normal development and in the repair of injured tissue. This review will summarize the biology of the various stem/progenitor cells, their effects on tissue repair in experimental models of lung and brain injury, the recent advances in our understanding of their mechanism of action, and the challenges that remain to be addressed before their eventual application to clinical care.

  16. Resonance, synchronization, and lexical redundancy in the expanding dynamics of brain stem neurons

    NASA Astrophysics Data System (ADS)

    Mandell, Arnold J.; Selz, Karen A.

    1993-11-01

    Interspike interval patterns of brain stem neurons that project directly or indirectly to much of the neocortex interactively influence electroencephalographically-defined states of consciousness and modulate patterns of temporal-spatial coherence, `binding,' in cortical field potential oscillations. Neurochemical classes of brain stem neurons manifest discriminable dynamical characteristics apart from the statistics of their firing rates. These sequences of interspike intervals are not well described by either harmonic functions or the Poisson statistics of renewal processes. We cast these patterns within the context of information bearing processes by using moment partitions and symbolic dynamics. We describe the expanding behavior of model and real brain stem neurons in relationship to states of resonance (the presence of complex singularities in the power spectrum with amplitudes related to the persistence of unstable fixed points in the nonexponential decay of correlations), synchronization (how closely the measure of maximal entropy comes to equaling the Sinai- Ruelle-Bowen area measure), and lexical redundancy (as repetitions of symbol subsequences).

  17. Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms

    NASA Astrophysics Data System (ADS)

    Tannenbaum, Emmanuel; Sherley, James L.; Shakhnovich, Eugene I.

    2005-04-01

    This paper develops a point-mutation model describing the evolutionary dynamics of a population of adult stem cells. Such a model may prove useful for quantitative studies of tissue aging and the emergence of cancer. We consider two modes of chromosome segregation: (1) random segregation, where the daughter chromosomes of a given parent chromosome segregate randomly into the stem cell and its differentiating sister cell and (2) “immortal DNA strand” co-segregation, for which the stem cell retains the daughter chromosomes with the oldest parent strands. Immortal strand co-segregation is a mechanism, originally proposed by [Cairns Nature (London) 255, 197 (1975)], by which stem cells preserve the integrity of their genomes. For random segregation, we develop an ordered strand pair formulation of the dynamics, analogous to the ordered strand pair formalism developed for quasispecies dynamics involving semiconservative replication with imperfect lesion repair (in this context, lesion repair is taken to mean repair of postreplication base-pair mismatches). Interestingly, a similar formulation is possible with immortal strand co-segregation, despite the fact that this segregation mechanism is age dependent. From our model we are able to mathematically show that, when lesion repair is imperfect, then immortal strand co-segregation leads to better preservation of the stem cell lineage than random chromosome segregation. Furthermore, our model allows us to estimate the optimal lesion repair efficiency for preserving an adult stem cell population for a given period of time. For human stem cells, we obtain that mispaired bases still present after replication and cell division should be left untouched, to avoid potentially fixing a mutation in both DNA strands.

  18. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review

    PubMed Central

    Nguyen, Patricia K.; Rhee, June-Wha; Wu, Joseph C.

    2017-01-01

    Importance Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for over 10% of deaths in the U.S. annually. Despite over a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is clinically effective and can be routinely implemented in clinical practice. Objective The purpose of this review is to describe the current progress in cardiac stem cell regenerative therapy using adult stem cells and highlight the merits and limitations of clinical trials performed to date. Evidence Review Information for this review was obtained through a search of PubMed and the Cochrane database for English language studies published between January 1, 2000 and April 20, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review. Findings Although adult stem cells were once believed to have the ability to create new heart tissue or grow blood vessels, preclinical studies suggest instead that these cells release cardio-protective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized controlled clinical trials, the majority of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methodology, discrepancies in reporting, and an over-reliance on surrogate endpoints. Conclusions and Relevance Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies. PMID:27557438

  19. Encoding of mechanical nociception differs in the adult and infant brain

    PubMed Central

    Fabrizi, Lorenzo; Verriotis, Madeleine; Williams, Gemma; Lee, Amy; Meek, Judith; Olhede, Sofia; Fitzgerald, Maria

    2016-01-01

    Newborn human infants display robust pain behaviour and specific cortical activity following noxious skin stimulation, but it is not known whether brain processing of nociceptive information differs in infants and adults. Imaging studies have emphasised the overlap between infant and adult brain connectome architecture, but electrophysiological analysis of infant brain nociceptive networks can provide further understanding of the functional postnatal development of pain perception. Here we hypothesise that the human infant brain encodes noxious information with different neuronal patterns compared to adults. To test this we compared EEG responses to the same time-locked noxious skin lance in infants aged 0–19 days (n = 18, clinically required) and adults aged 23–48 years (n = 21). Time-frequency analysis revealed that while some features of adult nociceptive network activity are present in infants at longer latencies, including beta-gamma oscillations, infants display a distinct, long latency, noxious evoked 18-fold energy increase in the fast delta band (2–4 Hz) that is absent in adults. The differences in activity between infants and adults have a widespread topographic distribution across the brain. These data support our hypothesis and indicate important postnatal changes in the encoding of mechanical pain in the human brain. PMID:27345331

  20. Neural Stem Cell Engraftment and Myelination in the Human Brain

    PubMed Central

    Gupta, Nalin; Henry, Roland G.; Strober, Jonathan; Kang, Sang-Mo; Lim, Daniel A.; Bucci, Monica; Caverzasi, Eduardo; Gaetano, Laura; Mandelli, Maria Luisa; Ryan, Tamara; Perry, Rachel; Farrell, Jody; Jeremy, Rita J.; Ulman, Mary; Huhn, Stephen L.; Barkovich, A. James; Rowitch, David H.

    2013-01-01

    Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year open-label phase 1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter. PMID:23052294

  1. Plastic adult stem cells: will they graduate from the school of hard knocks?

    PubMed

    Alison, Malcolm R; Poulsom, Richard; Otto, William R; Vig, Pamela; Brittan, Mairi; Direkze, Natalie C; Preston, Sean L; Wright, Nicholas A

    2003-02-15

    Notwithstanding the fact that adult bone marrow cell engraftment to epithelial organs seems a somewhat uncommon event, there is no doubt it does occur, and under appropriate conditions of a strong and positive selection pressure these cells will expand clonally and make a significant contribution to tissue replacement. Likewise, bone-marrow-derived cells can be amplified in vitro and differentiated into a multitude of tissues. These in essence are the goals of regenerative medicine using any source of stem cells, be it embryonic or adult. Despite such irrefutable evidence of what is possible, a veritable chorus of detractors of adult stem cell plasticity has emerged, some doubting its very existence, motivated perhaps by more than a little self-interest. The issues that have led to this state of affairs have included the inability to reproduce certain widely quoted data, one case where the apparent transdifferentiation was due to contamination of the donor tissue with haematopoietic cells and, most notoriously, extrapolating from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. While these issues need resolving, slamming this whole new field because not everything is crystal clear is not good science. The fact that a phenomenon is quite rare in no way mitigates against its very existence: asteroid collisions with the Earth are rare, but try telling the dinosaurs they do not occur! When such events do occur (transdifferentiation or collision), they certainly can make an impact.

  2. Empowering Adult Stem Cells for Myocardial Regeneration V2.0: Success in Small Steps.

    PubMed

    Broughton, Kathleen M; Sussman, Mark A

    2016-03-04

    Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells 4 years ago.(1) The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathological injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating state of affairs in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: "Success will never be a big step in the future. Success is a small step taken just now."

  3. The sexual identity of adult intestinal stem cells controls organ size and plasticity

    PubMed Central

    Hudry, Bruno; Khadayate, Sanjay; Miguel-Aliaga, Irene

    2016-01-01

    SUMMARY Sex differences in physiology and disease susceptibility are commonly attributed to developmental and/or hormonal factors, but there is increasing realisation that cell-intrinsic mechanisms play important and persistent roles1,2. Here we use the Drosophila melanogaster intestine to investigate the nature and significance of cellular sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncover its key roles in controlling organ size, its reproductive plasticity and its response to genetically induced tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms, which control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognised. PMID:26887495

  4. Myf5 haploinsufficiency reveals distinct cell fate potentials for adult skeletal muscle stem cells.

    PubMed

    Gayraud-Morel, Barbara; Chrétien, Fabrice; Jory, Aurélie; Sambasivan, Ramkumar; Negroni, Elisa; Flamant, Patricia; Soubigou, Guillaume; Coppée, Jean-Yves; Di Santo, James; Cumano, Ana; Mouly, Vincent; Tajbakhsh, Shahragim

    2012-04-01

    Skeletal muscle stem cell fate in adult mice is regulated by crucial transcription factors, including the determination genes Myf5 and Myod. The precise role of Myf5 in regulating quiescent muscle stem cells has remained elusive. Here we show that most, but not all, quiescent satellite cells express Myf5 protein, but at varying levels, and that resident Myf5 heterozygous muscle stem cells are more primed for myogenic commitment compared with wild-type satellite cells. Paradoxically however, heterotypic transplantation of Myf5 heterozygous cells into regenerating muscles results in higher self-renewal capacity compared with wild-type stem cells, whereas myofibre regenerative capacity is not altered. By contrast, Pax7 haploinsufficiency does not show major modifications by transcriptome analysis. These observations provide a mechanism linking Myf5 levels to muscle stem cell heterogeneity and fate by exposing two distinct and opposing phenotypes associated with Myf5 haploinsufficiency. These findings have important implications for how stem cell fates can be modulated by crucial transcription factors while generating a pool of responsive heterogeneous cells.

  5. Physicochemical Control of Adult Stem Cell Differentiation: Shedding Light on Potential Molecular Mechanisms

    DTIC Science & Technology

    2010-01-01

    applications, including tissue engineering, requires an understanding of the cell-cell and cell-environment interactions. To this end, recent efforts have been...restricted locations to allow continuation of the cycle of life [1]. These tissue -specific stem cells have been identified in the bone marrow [2], brain [3...relatively easy to isolate and differentiate into neuronal cells, and therefore may be useful for tissue engineering strategies to repair and regenerate

  6. A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

    PubMed Central

    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. PMID:24936790

  7. Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke.

    PubMed

    Chang, Alice Y W; Li, Faith C H; Huang, Chi-Wei; Wu, Julie C C; Dai, Kuang-Yu; Chen, Chang-Han; Li, Shau-Hsuan; Su, Chia-Hao; Wu, Re-Wen

    2014-11-01

    Pressor response after stroke commonly leads to early death or susceptibility to stroke recurrence, and detailed mechanisms are still lacking. We assessed the hypothesis that the renin-angiotensin system contributes to pressor response after stroke by differential modulation of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) in the rostral ventrolateral medulla (RVLM), a key brain stem site that maintains blood pressure. We also investigated the beneficial effects of a novel renin inhibitor, aliskiren, against stroke-elicited pressor response. Experiments were performed in male adult Sprague-Dawley rats. Stroke induced by middle cerebral artery occlusion elicited significant pressor response, accompanied by activation of angiotensin II (Ang II)/type I receptor (AT1R) and AT2R signaling, depression of Ang-(1-7)/MasR and Ang IV/AT4R cascade, alongside augmentation of MCP-1/C-C chemokine receptor 2 (CCR2) signaling and neuroinflammation in the RVLM. Stroke-elicited pressor response was significantly blunted by antagonism of AT1R, AT2R or MCP-1/CCR2 signaling, and eliminated by applying Ang-(1-7) or Ang IV into the RVLM. Furthermore, stroke-activated MCP-1/CCR2 signaling was enhanced by AT1R and AT2R activation, and depressed by Ang-(1-7)/MasR and Ang IV/AT4R cascade. Aliskiren inhibited stroke-elicited pressor response via downregulating MCP-1/CCR2 activity and reduced neuroinflammation in the RVLM; these effects were potentiated by Ang-(1-7) or Ang IV. We conclude that whereas Ang II/AT1R or Ang II/AT2R signaling in the brain stem enhances, Ang-(1-7)/MasR or Ang IV/AT4R antagonizes pressor response after stroke by differential modulations of MCP-1 in the RVLM. Furthermore, combined administration of aliskiren and Ang-(1-7) or Ang IV into the brain stem provides more effective amelioration of stroked-induced pressor response.

  8. Behavioral and magnetoencephalographic correlates of plasticity in the adult human brain

    PubMed Central

    Ramachandran, V. S.

    1993-01-01

    Recent behavioral and physiological evidence suggests that even brief sensory deprivation can lead to the rapid emergence of new and functionally effective neural connections in the adult human brain. Images Fig. 2 PMID:8248123

  9. Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

    PubMed

    Chung, Kyung Min; Park, Hyunhee; Jung, Seonghee; Ha, Shinwon; Yoo, Seung-Jun; Woo, Hanwoong; Lee, Hyang Ju; Kim, Seong Who; Kim, Eun-Kyoung; Moon, Cheil; Yu, Seong-Woon

    2015-10-01

    Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death.

  10. Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model.

    PubMed

    Lee, Hong J; Lim, In J; Lee, Min C; Kim, Seung U

    2010-11-15

    Intracerebral hemorrhage (ICH) is a lethal stroke type; mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, so an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and promote functional recovery in rat ICH model, and others have shown that intracerebral infusion of brain-derived neurotrophic factor (BDNF) results in improved structural and functional outcome from cerebral ischemia. We postulated that human NSCs overexpressing BDNF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs and increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by injection of bacterial collagenase into striatum. The HB1.F3.BDNF (F3.BDNF) human NSC line produces sixfold higher amounts of BDNFF over the parental F3 cell line in vitro, induces behavioral improvement, and produces a threefold increase in cell survival at 2 weeks and 8 weeks posttransplantation. Brain transplantation of human NSCs overexpressing BDNF provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results indicate that the F3.BDNF human NSCs should be of great value as a cellular source for experimental studies involving cellular therapy for human neurological disorders, including ICH.

  11. Adult Adipose-Derived Stem Cell Attachment to Biomaterials

    PubMed Central

    Prichard, Heather L; Reichert, William M; Klitzman, Bruce

    2007-01-01

    Attachment of adipose-derived stem cells (ASC) to biomaterials prior to implantation is a possible strategy for mediating inflammation and wound healing. In this study, the ASC percent coverage was measured on common medical grade biosensor materials subjected to different surface treatments. Cell coverage on silicone elastomer (poly dimethylsiloxane) was below 20% for all surface treatments. Polyimide (Kapton), polyurethane (Pellethane) and tissue culture polystyrene all exhibited >50% coverage for surfaces treated with fibronectin (Fn), fibronectin plus avidin/biotin (dual ligand), and oxygen plasma plus fibronectin treatments (Fn O2). The fibronectin treatment performed as well or better on polyimide, polyurethane, and tissue culture polystyrene compared to the dual ligand and fibronectin oxygen plasma treated surfaces. Cell detachment with increasing shear stresses was <25% for each attachment method on both polyimide and polyurethane. The effects of attachment methods on the basic cell functions of proliferation, metabolism, ATP concentration, and caspase-3 activity were analyzed yielding proliferation profiles that were very similar among all of the materials. No significant differences in metabolism, intracellular ATP, or intracellular caspase-3 activity were observed for any of the attachment methods on either polyimide or polyurethane. PMID:17074385

  12. A reverse transfection technology to genetically engineer adult stem cells.

    PubMed

    Okazaki, Arimichi; Jo, Jun-Ichiro; Tabata, Yasuhiko

    2007-02-01

    A new non-viral method of gene transfection was designed to enhance the level of gene expression for rat mesenchymal stem cells (MSCs). Pullulan was cationized using chemical introduction of spermine to prepare cationized pullulan of non-viral carrier (spermine-pullulan). The spermine-pullulan was complexed with a plasmid deoxyribonucleic acid (DNA) of luciferase and coated on the surface of culture substrate together with Pronectin of artificial cell adhesion protein. MSCs were cultured and transfected on the complex-coated substrate (reverse transfection), and the level and duration of gene expression were compared with those of MSCs transfected by culturing in the medium containing the plasmid DNA-spermine-pullulan complex (conventional method). The reverse transfection method enhanced and prolonged gene expression significantly more than did the conventional method. The reverse method permitted the transfection culture of MSCs in the presence of serum, in contrast to the conventional method, which gave cells a good culture condition to lower cytotoxicity. The reverse transfection was carried out for a non-woven fabric of polyethylene terephthalate (PET) coated with the complex and Pronectin using agitation and stirring culture methods. The two methods enhanced the level and duration of gene expression for MSCs significantly more than did the static method. It is possible that medium circulation improves the culture conditions of cells in terms of oxygen and nutrition supply and waste excretion, resulting in enhanced gene expression.

  13. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

    PubMed Central

    Liu, He; Song, Ni

    2016-01-01

    Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and brain tumors. PMID:27375363

  14. Cytoarchitecture, Proliferative Activity and Neuroblast Migration in the Subventricular Zone and Lateral Ventricle Extension of the Adult Guinea Pig Brain.

    PubMed

    Jara, Nery; Cifuentes, Manuel; Martínez, Fernando; Salazar, Katterine; Nualart, Francisco

    2016-10-01

    In the mouse brain, neuroblasts generated in the subventricular zone (SVZ) migrate to the olfactory bulb (OB) through the rostral migratory stream (RMS). Although the RMS is not present in the human brain, a migratory pathway that is organized around a ventricular cavity that reaches the OB has been reported. A similar cavity, the lateral ventricle extension (LVE), is found in the adult guinea pig brain. Therefore, we analyzed cytoarchitecture, proliferative activity and precursor cell migration in the SVZ and LVE of 1-, 6- and 12-month-old guinea pigs. In young animals, we used confocal spectral and transmission electron microscopy to identify neuroblasts, astrocytes, and progenitor cells in the SVZ and LVE. Analysis of peroxidase diffusion demonstrated that the LVE was a continuous cavity lined by ependymal cells and surrounded by neuroblasts. Precursor cells were mostly located in the SVZ and migrated from the SVZ to the OB through the LVE. Finally, analysis of 6- and 12-month-old guinea pigs revealed that the LVE was preserved in older animals; however, the number of neurogenic cells was significantly reduced. Consequently, we propose that the guinea pig brain may be used as a new neurogenic model with increased similarity to humans, given that the LVE connects the LV with the OB, as has been described in humans, and that the LVE works a migratory pathway. Stem Cells 2016;34:2574-2586.

  15. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

    PubMed

    Qian, Qi; Liu, Qiuji; Zhou, Dongming; Pan, Hongyu; Liu, Zhiwei; He, Fangping; Ji, Suying; Wang, Dongpi; Bao, Wangxiao; Liu, Xinyi; Liu, Zhaoling; Zhang, Heng; Zhang, Xiaoqin; Zhang, Ling; Wang, Mingkai; Xu, Ying; Huang, Fude; Luo, Benyan; Sun, Binggui

    2017-02-13

    Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a(f/f) mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL(+) cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

  16. Health Problems Precede Traumatic Brain Injury in Older Adults

    PubMed Central

    Dams-O’Connor, Kristen; Gibbons, Laura E; Landau, Alexandra; Larson, Eric B; Crane, Paul K.

    2016-01-01

    Objectives To evaluate whether indices of pre-injury health and functioning were associated with risk for incident traumatic brain injury (TBI) with loss of consciousness (LOC), and evaluated health-related factors associated with mortality among those with an incident TBI. Design Prospective community cohort study. Setting Group Health, Seattle Washington. Participants 3,363 individuals aged 65 and older with no self-reported prior TBI with LOC were enrolled and followed every 2 years for an average of 7.5 years (range 0–18 years). Measurements We used Weibull survival models to evaluate baseline and time-varying predictors of incident TBI with LOC, including measures of depression, activities of daily living, cerebrovascular disease, and disease comorbidity. Results In an adjusted multivariate model, baseline depression symptoms as measured by CES-D score (hazard ratio (HR) and 95% confidence interval (CI) for 4 points = 1.34 (1.13, 1.58); p<0.05) and baseline impairment in activities of daily living (ADL; HR (95% CI) = 2.37 (1.24, 4.53); p<0.01) were associated with incident TBI. In a model that included time-dependent covariates, cerebrovascular disease at the previous visit (HR (95% CI) = 2.28 (1.37, 3.78); p<0.01), CES-D score the previous visit (HR for 4 points (95% CI) = 1.23 (1.02, 1.49); p<0.05) and baseline impairment in ADL (HR (95% CI) 2.14 (1.11, 4.13); p<0.05) predicted incident TBI. Of factors considered, cerebrovascular disease and ADL impairment were associated with earlier mortality among those with an incident TBI with LOC. Conclusion Indices of health, mood, and functional status predict incident TBI with LOC in older adults. These findings may have implications for injury prevention and post-injury clinical management. PMID:26925541

  17. Monte Carlo simulation of light propagation in the adult brain

    NASA Astrophysics Data System (ADS)

    Mudra, Regina M.; Nadler, Andreas; Keller, Emanuella; Niederer, Peter

    2004-06-01

    When near infrared spectroscopy (NIRS) is applied noninvasively to the adult head for brain monitoring, extra-cerebral bone and surface tissue exert a substantial influence on the cerebral signal. Most attempts to subtract extra-cerebral contamination involve spatially resolved spectroscopy (SRS). However, inter-individual variability of anatomy restrict the reliability of SRS. We simulated the light propagation with Monte Carlo techniques on the basis of anatomical structures determined from 3D-magnetic resonance imaging (MRI) exhibiting a voxel resolution of 0.8 x 0.8 x 0.8 mm3 for three different pairs of T1/T2 values each. The MRI data were used to define the material light absorption and dispersion coefficient for each voxel. The resulting spatial matrix was applied in the Monte Carlo Simulation to determine the light propagation in the cerebral cortex and overlaying structures. The accuracy of the Monte Carlo Simulation was furthermore increased by using a constant optical path length for the photons which was less than the median optical path length of the different materials. Based on our simulations we found a differential pathlength factor (DPF) of 6.15 which is close to with the value of 5.9 found in the literature for a distance of 4.5cm between the external sensors. Furthermore, we weighted the spatial probability distribution of the photons within the different tissues with the probabilities of the relative blood volume within the tissue. The results show that 50% of the NIRS signal is determined by the grey matter of the cerebral cortex which allows us to conclude that NIRS can produce meaningful cerebral blood flow measurements providing that the necessary corrections for extracerebral contamination are included.

  18. Effects of addictive drugs on adult neural stem/progenitor cells

    PubMed Central

    Xu, Chi; Loh, Horace H.; Law, Ping-Yee

    2015-01-01

    Neural stem/progenitor cells (NSPCs) undergo a series of developmental processes before giving rise to newborn neurons, astrocytes and oligodendrocytes in adult neurogenesis. During the past decade, the role of NSPCs has been highlighted by studies on adult neurogenesis modulated by addictive drugs. It has been proven that these drugs regulate the proliferation, differentiation and survival of adult NSPCs in different manners, which results in the varying consequences of adult neurogenesis. The effects of addictive drugs on NSPCs are exerted via a variety of different mechanisms and pathways, which interact with one another and contribute to the complexity of NSPC regulation. Here, we review the effects of different addictive drugs on NSPCs, and the related experimental methods and paradigms. We also discuss the current understanding of major signaling molecules, especially the putative common mechanisms, underlying such effects. Finally, we review the future directions of research in this area. PMID:26468052

  19. Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand.

    PubMed

    Rizzoti, Karine; Akiyama, Haruhiko; Lovell-Badge, Robin

    2013-10-03

    Pituitary hormone deficiencies, with Growth Hormone deficiency being most frequent (1 in 3,500-10,000 births), cause significant morbidity. Regeneration of missing endocrine cells would be a significant improvement over hormone replacement therapies, which incur side effects and do not mimic physiological secretion patterns. Recent in vitro studies have identified a population of adult pituitary progenitors that express the HMG box transcription factors SOX2 and SOX9. Here, we apply cell-lineage tracing analysis to demonstrate that SOX2- and SOX9-expressing progenitors can self-renew and give rise to endocrine cells in vivo, suggesting that they are tissue stem cells. Moreover, we show that they can become mobilized and differentiate into the appropriate endocrine cell types in response to physiological stress. Our results highlight the pituitary as a model for exploring how physiological changes influence stem cell behavior and suggest that manipulation of endogenous pituitary stem cells is a potential therapeutic strategy for pituitary deficiencies.

  20. Muscle regeneration by adipose tissue-derived adult stem cells attached to injectable PLGA spheres.

    PubMed

    Kim, MiJung; Choi, Yu Suk; Yang, Seung Hye; Hong, Hea-Nam; Cho, Sung-Woo; Cha, Sang Myun; Pak, Jhang Ho; Kim, Chan Wha; Kwon, Seog Woon; Park, Chan Jeoung

    2006-09-22

    The [corrected] use of adult stem cells for cell-based tissue engineering and regeneration strategies represents a promising approach for skeletal muscle repair. We have evaluated the combination of adipose tissue-derived adult stem cells (ADSCs) obtained from autologous liposuction and injectable poly(lactic-co-glycolic acid) (PLGA) spheres for muscle regeneration. ADSCs attached to PLGA spheres and PLGA spheres alone were cultured in myogenic medium for 21 days and injected subcutaneously into the necks of nude mice. After 30 and 60 days, the mice were sacrificed, and newly formed tissues were analyzed by immunostaining, H and E staining, and RT-PCR. We found that ADSCs attached to PLGA spheres, but not PLGA spheres alone, were able to generate muscle tissue. These findings suggest that ADSCs and PLGA spheres are useful materials for muscle tissue engineering and that their combination can be used in clinical settings for muscle regeneration.

  1. The Par complex and integrins direct asymmetric cell division in adult intestinal stem cells.

    PubMed

    Goulas, Spyros; Conder, Ryan; Knoblich, Juergen A

    2012-10-05

    The adult Drosophila midgut is maintained by intestinal stem cells (ISCs) that generate both self-renewing and differentiating daughter cells. How this asymmetry is generated is currently unclear. Here, we demonstrate that asymmetric ISC division is established by a unique combination of extracellular and intracellular polarity mechanisms. We show that Integrin-dependent adhesion to the basement membrane induces cell-intrinsic polarity and results in the asymmetric segregation of the Par proteins Par-3, Par-6, and aPKC into the apical daughter cell. Cell-specific knockdown and overexpression experiments suggest that increased activity of aPKC enhances Delta/Notch signaling in one of the two daughter cells to induce terminal differentiation. Perturbing this mechanism or altering the orientation of ISC division results in the formation of intestinal tumors. Our data indicate that mechanisms for intrinsically asymmetric cell division can be adapted to allow for the flexibility in lineage decisions that is required in adult stem cells.

  2. Embryonic origin of adult stem cells required for tissue homeostasis and regeneration.

    PubMed

    Davies, Erin L; Lei, Kai; Seidel, Christopher W; Kroesen, Amanda E; McKinney, Sean A; Guo, Longhua; Robb, Sofia Mc; Ross, Eric J; Gotting, Kirsten; Alvarado, Alejandro Sánchez

    2017-01-10

    Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration.

  3. Organoids from adult liver and pancreas: Stem cell biology and biomedical utility.

    PubMed

    Hindley, Christopher J; Cordero-Espinoza, Lucía; Huch, Meritxell

    2016-12-15

    The liver and pancreas are critical organs maintaining whole body metabolism. Historically, the expansion of adult-derived cells from these organs in vitro has proven challenging and this in turn has hampered studies of liver and pancreas stem cell biology, as well as being a roadblock to disease modelling and cell replacement therapies for pathologies in these organs. Recently, defined culture conditions have been described which allow the in vitro culture and manipulation of adult-derived liver and pancreatic material. Here we review these systems and assess their physiological relevance, as well as their potential utility in biomedicine.

  4. Notch signaling induces retinal stem-like properties in perinatal neural retina progenitors and promotes symmetric divisions in adult retinal stem cells.

    PubMed

    Balenci, Laurent; van der Kooy, Derek

    2014-02-01

    Understanding the mechanisms regulating retinal stem cell (RSC) activity is fundamental for future stem cell-based therapeutic purposes. By combining gain and loss of function approaches, we addressed whether Notch signaling may play a selective role in retinal stem versus retinal progenitor cells in both developing and adult eyes. Inhibition of either Notch or fibroblast growth factor signaling reduced proliferation of retinal stem and retinal progenitor cells, and inhibited RSC self-renewal. Conversely, exogenous Delta-like 3 and direct intrinsic Notch activation stimulated expansionary symmetric divisions in adult RSCs with the concomitant upregulation of Hes5. Knocking down Hes5 expression specifically decreased the numbers, but not the diameters, of adult RSC primary spheres, indicating that HES5 is the downstream effector of Notch receptor in controlling adult RSC proliferation. In addition, constitutive Notch activation induced retinal stem-like asymmetric self-renewal properties, with no expansion (no symmetrical division) in perinatal neural retina progenitor cells. These findings highlight central roles of Notch signaling activity in regulating the modes of division of retinal stem and retinal progenitor cells.

  5. Over Expression of BCL2 and Low Expression of Caspase 8 Related to TRAIL Resistance in Brain Cancer Stem Cells.

    PubMed

    Qi, Ling; Ren, Kuang; Fang, Fang; Zhao, Dong-Hai; Yang, Ning-Jiang; Li, Yan

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been investigated as an effective agent to treat various cancers. Cancer stem cells are resistant to TRAIL treatment, but the mechanism of TRAIL resistance remains unknown. In this study, brain cancer stem cells were isolated by CD133 magnetic sorting, and the number of CD133 positive cells detected by flow cytometry. The self-renewing capacity of brain cancer stem cells was examined by a neurosphere formation assay, and the percentage of cell death after TRAIL treatment was examined by an MTS assay. Expression of DR5, FADD, caspase 8 and BCL2 proteins was detected by western blot. The amount of CD133 positive cells was enriched to 71% after CD133 magnetic sorting. Brain cancer stem cell neurosphere formation was significantly increased after TRAIL treatment. TRAIL treatment also reduced the amount of viable cells and this decrease was inhibited by a caspase 8 inhibitor or by the pan-caspase inhibitor z-VAD (P<0.05). Brain cancer stem cells expressed lower levels caspase 8 protein and higher levels of BCL2 protein when compared with CD133 negative cells (P<0.05). Our data suggest that TRAIL resistance is related to overexpression of BCL2 and low expression of caspase 8 which limit activation of caspase 8 in brain cancer stem cells.

  6. Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity

    PubMed Central

    Ulloa-Montoya, Fernando; Kidder, Benjamin L; Pauwelyn, Karen A; Chase, Lucas G; Luttun, Aernout; Crabbe, Annelies; Geraerts, Martine; Sharov, Alexei A; Piao, Yulan; Ko, Minoru SH; Hu, Wei-Shou; Verfaillie, Catherine M

    2007-01-01

    Background Recently, several populations of postnatal stem cells, such as multipotent adult progenitor cells (MAPCs), have been described that have broader differentiation ability than classical adult stem cells. Here we compare the transcriptome of pluripotent embryonic stem cells (ESCs), MAPCs, and lineage-restricted mesenchymal stem cells (MSCs) to determine their relationship. Results Applying principal component analysis, non-negative matrix factorization and k-means clustering algorithms to the gene-expression data, we identified a unique gene-expression profile for MAPCs. Apart from the ESC-specific transcription factor Oct4 and other ESC transcripts, some of them associated with maintaining ESC pluripotency, MAPCs also express transcripts characteristic of early endoderm and mesoderm. MAPCs do not, however, express Nanog or Sox2, two other key transcription factors involved in maintaining ESC properties. This unique molecular signature was seen irrespective of the microarray platform used and was very similar for both mouse and rat MAPCs. As MSC-like cells isolated under MAPC conditions are virtually identical to MSCs, and MSCs cultured in MAPC conditions do not upregulate MAPC-expressed transcripts, the MAPC signature is cell-type specific and not merely the result of differing culture conditions. Conclusion Multivariate analysis techniques clustered stem cells on the basis of their expressed gene profile, and the genes determining this clustering reflected the stem cells' differentiation potential in vitro. This comparative transcriptome analysis should significantly aid the isolation and culture of MAPCs and MAPC-like cells, and form the basis for studies to gain insights into genes that confer on these cells their greater developmental potency. PMID:17683608

  7. Treatment Efficacy: Cognitive-Communicative Disorders Resulting from Traumatic Brain Injury in Adults.

    ERIC Educational Resources Information Center

    Coelho, Carl A.; And Others

    1996-01-01

    This article discusses adults with brain injuries and resulting cognitive communicative disorders. The incidence of brain injuries, the effects of cognitive-communication disorders, the role of the speech-language pathologist, the benefits of treatment, and the effects of different treatments are discussed. Charts are included that summarize…

  8. Adult marrow-derived very small embryonic-like stem cells and tissue engineering.

    PubMed

    Kucia, Magda; Zuba-Surma, Ewa K; Wysoczynski, Marcin; Wu, Wan; Ratajczak, Janina; Machalinski, Boguslaw; Ratajczak, Mariusz Z

    2007-10-01

    A population of CXCR4(+) lin(-) CD45(-) cells that express SSEA, Oct-4 and Nanog has been identified in adult bone marrow. These cells are very small and display several features typical for primary embryonic stem cells such as: i) a large nuclei surrounded by a narrow rim of cytoplasm; ii) open-type chromatin (euchromatin); and iii) high telomerase activity. These cells were named very small embryonic-like stem cells (VSEL-SC). The authors hypothesized that they are direct descendants of the germ lineage. Germ lineage, in order to pass genes on to the next generation, has to create soma and thus becomes a 'mother lineage' for all somatic cell lineages present in the adult body. Germ potential is established after conception in a totipotent zygote and retained subsequently during development in blastomers of morula, cells form the inner cell mass of blastocyst, epiblast and population of primordial germ cells. The authors envision that VSEL-SC are epiblast-derived pluripotent stem cells and could potentially become a less-controversial source of stem cells for regeneration.

  9. Spontaneous transformation of adult mesenchymal stem cells from cynomolgus macaques in vitro

    SciTech Connect

    Ren, Zhenhua; Wang, Jiayin; Zhu, Wanwan; Guan, Yunqian; Zou, Chunlin; Chen, Zhiguo; Zhang, Y. Alex

    2011-12-10

    Mesenchymal stem cells (MSCs) have shown potential clinical utility in cell therapy and tissue engineering, due to their ability to proliferate as well as to differentiate into multiple lineages, including osteogenic, adipogenic, and chondrogenic specifications. Therefore, it is crucial to assess the safety of MSCs while extensive expansion ex vivo is a prerequisite to obtain the cell numbers for cell transplantation. Here we show that MSCs derived from adult cynomolgus monkey can undergo spontaneous transformation following in vitro culture. In comparison with MSCs, the spontaneously transformed mesenchymal cells (TMCs) display significantly different growth pattern and morphology, reminiscent of the characteristics of tumor cells. Importantly, TMCs are highly tumorigenic, causing subcutaneous tumors when injected into NOD/SCID mice. Moreover, no multiple differentiation potential of TMCs is observed in vitro or in vivo, suggesting that spontaneously transformed adult stem cells may not necessarily turn into cancer stem cells. These data indicate a direct transformation of cynomolgus monkey MSCs into tumor cells following long-term expansion in vitro. The spontaneous transformation of the cultured cynomolgus monkey MSCs may have important implications for ongoing clinical trials and for models of oncogenesis, thus warranting a more strict assessment of MSCs prior to cell therapy. -- Highlights: Black-Right-Pointing-Pointer Spontaneous transformation of cynomolgus monkey MSCs in vitro. Black-Right-Pointing-Pointer Transformed mesenchymal cells lack multipotency. Black-Right-Pointing-Pointer Transformed mesenchymal cells are highly tumorigenic. Black-Right-Pointing-Pointer Transformed mesenchymal cells do not have the characteristics of cancer stem cells.

  10. Autologous Transplantation of Bone Marrow Adult Stem Cells for the Treatment of Idiopathic Dilated Cardiomyopathy

    PubMed Central

    Westphal, Ricardo João; Bueno, Ronaldo Rocha Loures; Galvão, Paulo Bezerra de Araújo; Zanis Neto, José; Souza, Juliano Mendes; Guérios, Ênio Eduardo; Senegaglia, Alexandra Cristina; Brofman, Paulo Roberto; Pasquini, Ricardo; da Cunha, Claudio Leinig Pereira

    2014-01-01

    Background Morbimortality in patients with dilated idiopathic cardiomyopathy is high, even under optimal medical treatment. Autologous infusion of bone marrow adult stem cells has shown promising preliminary results in these patients. Objective Determine the effectiveness of autologous transplantation of bone marrow adult stem cells on systolic and diastolic left ventricular function, and on the degree of mitral regurgitation in patients with dilated idiopathic cardiomyopathy in functional classes NYHA II and III. Methods We administered 4,54 x 108 ± 0,89 x 108 bone marrow adult stem cells into the coronary arteries of 24 patients with dilated idiopathic cardiomyopathy in functional classes NYHA II and III. Changes in functional class, systolic and diastolic left ventricular function and degree of mitral regurgitation were assessed after 3 months, 6 months and 1 year. Results During follow-up, six patients (25%) improved functional class and eight (33.3%) kept stable. Left ventricular ejection fraction improved 8.9%, 9.7% e 13.6%, after 3, 6 and 12 months (p = 0.024; 0.017 and 0.018), respectively. There were no significant changes neither in diastolic left ventricular function nor in mitral regurgitation degree. A combined cardiac resynchronization and implantable cardioversion defibrillation was implanted in two patients (8.3%). Four patients (16.6%) had sudden death and four patients died due to terminal cardiac failure. Average survival of these eight patients was 2.6 years. Conclusion Intracoronary infusion of bone marrow adult stem cells was associated with an improvement or stabilization of functional class and an improvement in left ventricular ejection fraction, suggesting the efficacy of this intervention. There were no significant changes neither in left ventricular diastolic function nor in the degree of mitral regurgitation. PMID:25590932

  11. Activation of expression of brain-derived neurotrophic factor at the site of implantation of allogenic and xenogenic neural stem (progenitor) cells in rats with ischemic cortical stroke.

    PubMed

    Chekhonin, V P; Lebedev, S V; Volkov, A I; Pavlov, K A; Ter-Arutyunyants, A A; Volgina, N E; Savchenko, E A; Grinenko, N F; Lazarenko, I P

    2011-02-01

    Ischemic stroke was modeled in the sensorimotor zone of the brain cortex in adult rats. Rat embryonic nervous tissue, neural stem cells from human olfactory epithelium, and rat fibroblasts (cell control) were implanted into the peri-infarction area of rats of different groups immediately after stroke modeling. Expression of BDNF mRNA was analyzed 7 days after surgery by real-time PCR. BDNF expression in cell preparation before their implantation was minimum. The expression of BDNF mRNA increased by 5-6 times in the areas of implantation of rat fibroblasts and human olfactory epithelium and by 23 times in the area of implantation of rat embryonic nervous tissue compared to periinfarction areas without cell implantation. These findings confirm the possibility of realization of the therapeutic effects of neural stem cells via expression of trophic factors.

  12. The doublecortin-expressing population in the developing and adult brain contains multipotential precursors in addition to neuronal-lineage cells.

    PubMed

    Walker, Tara L; Yasuda, Takahiro; Adams, David J; Bartlett, Perry F

    2007-04-04

    Doublecortin (DCX) has recently been promulgated as a selective marker of cells committed to the neuronal lineage in both the developing and the adult brain. To explore the potential of DCX-positive (DCX+) cells more stringently, these cells were isolated by flow cytometry from the brains of transgenic mice expressing green fluorescent protein under the control of the DCX promoter in embryonic, early postnatal, and adult animals. It was found that virtually all of the cells (99.9%) expressing high levels of DCX (DCX(high)) in the embryonic brain coexpressed the neuronal marker betaIII-tubulin and that this population contained no stem-like cells as demonstrated by lack of neurosphere formation in vitro. However, the DCX+ population from the early postnatal brain and the adult subventricular zone and hippocampus, which expressed low levels of DCX (DCX(low)), was enriched for neurosphere-forming cells, with only a small subpopulation of these cells coexpressing the neuronal markers betaIII-tubulin or microtubule-associated protein 2. Similarly, the DCX(low) population from embryonic day 14 (E14) brain contained neurosphere-forming cells. Only the postnatal cerebellum and adult olfactory bulb contained some DCX(high) cells, which were shown to be similar to the E14 DCX(high) cells in that they had no stem cell activity. Electrophysiological studies confirmed the heterogeneous nature of DCX+ cells, with some cells displaying characteristics of immature or mature neurons, whereas others showed no neuronal characteristics whatsoever. These results indicate that DCX(high) cells, regardless of location, are restricted to the neuronal lineage or are bone fide neurons, whereas some DCX(low) cells retain their multipotentiality.

  13. A Hyaluronic Acid-Rich Node and Duct System in Which Pluripotent Adult Stem Cells Circulate.

    PubMed

    Rai, Rajani; Chandra, Vishal; Kwon, Byoung S

    2015-10-01

    Regenerative medicine is in demand of adult pluripotent stem cells (PSCs). The "Bonghan System (BHS)" was discovered and suggested to contain cells with regenerative capacity in the early 1960s. It had been ignored for a long time due to the lack of sufficient details of experiments, but about 37 years after the initial report, the BHS was rediscovered and named as the "primo vascular system." Recently, we have discovered a similar structure, which contained a high level of hyaluronic acid, and hence, named the structure as hyaluronic acid-rich node and duct system (HAR-NDS). Here we discuss the HAR-NDS concept starting from the discovery of BHS, and findings pointing to its importance in regenerative medicine. This HAR-NDS contained adult PSCs, called node and duct stem cells (NDSCs), which appeared to circulate in it. We describe the evidence that NDSCs can differentiate into hemangioblasts that further produced differentiated blood cells. The NDSCs had a potential to differentiate into neuronal cells and hepatocytes; thus, NDSCs had a capability to become cells from all three germ layers. This system appears to be a promising alternative source of adult stem cells that can be easily delivered to their target tissues and participate in tissue regeneration.

  14. Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary

    PubMed Central

    Yoshida, Saishu; Kato, Takako; Kato, Yukio

    2016-01-01

    The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex-determining region Y-box 2 (SOX2)+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+-pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche) and the dense cell clusters scattering in the parenchyma (parenchymal-niche). However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes. PMID:26761002

  15. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity.

    PubMed

    Rasper, Michael; Schäfer, Andrea; Piontek, Guido; Teufel, Julian; Brockhoff, Gero; Ringel, Florian; Heindl, Stefan; Zimmer, Claus; Schlegel, Jürgen

    2010-10-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.

  16. Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse.

    PubMed

    Meng, Xing-Li; Shen, Jin-Song; Ohashi, Toya; Maeda, Hiroshi; Kim, Seung Up; Eto, Yoshikatsu

    2003-10-15

    In the present study, we investigated the feasibility of using human neural stem cells (NSCs) in the treatment of diffuse central nervous system (CNS) alterations in a murine model of mucopolysaccharidosis VII (MPS VII), a lysosomal storage disease caused by a genetic defect in the beta-glucuronidase gene. An immortalized NSC line derived from human fetal telencephalon was genetically engineered to overexpress beta-glucuronidase and transplanted into the cerebral ventricles of neonatal MPS VII mouse. Transplanted human NSCs were found to integrate and migrate in the host brain and to produce large amount of beta-glucuronidase. Brain contents of the substrates of beta-glucuronidase were reduced to nearly normal levels, and widespread clearing of lysosomal storage was observed in the MPS VII mouse brain at 25 days posttransplantation. The number of engrafted cells decreased markedly after the transplantation, and it appears that the major cause of the cell death was not the immune response of the host but apoptotic cell death of grafted human NSCs. Results showed that human NSCs would serve as a useful gene transfer vehicle for the treatment of diffuse CNS lesions in human lysosomal storage diseases and are potentially applicable in the treatment of patients suffering from neurological disorders.

  17. Future Concerns of Adult Siblings of Persons with Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Degeneffe, Charles Edmund; Olney, Marjorie F.

    2008-01-01

    This study examined future concerns conveyed by adult siblings who provided regular caregiving support to their brothers and sisters with traumatic brain injury (TBI). The authors surveyed a national sample of 280 adult siblings of persons with TBI. Using a constant comparative approach to text analysis, the authors analyzed responses to the…

  18. Correlates of Depression in Adult Siblings of Persons with Traumatic Brain Injury

    ERIC Educational Resources Information Center

    Degeneffe, Charles Edmund; Lynch, Ruth Torkelson

    2006-01-01

    Using Pearlin's stress process model, this study examined correlates of depression in 170 adult siblings of persons with traumatic brain injury (TBI). Approximately 39% of adult sibling participants evinced "Center for Epidemiologic Studies-Depression" (CES-D; Radloff, 1977) scores indicating clinically significant depressive symptoms. Background…

  19. Development of a Conceptual Model to Predict Physical Activity Participation in Adults with Brain Injuries

    ERIC Educational Resources Information Center

    Driver, Simon

    2008-01-01

    The purpose was to examine psychosocial factors that influence the physical activity behaviors of adults with brain injuries. Two differing models, based on Harter's model of self-worth, were proposed to examine the relationship between perceived competence, social support, physical self-worth, affect, and motivation. Adults numbering 384 with…

  20. Lymphatic Reprogramming of Adult Endothelial Stem Cells for a Cell-Based Therapy for Lymphedema in Breast Cancer Patients

    DTIC Science & Technology

    2008-09-01

    Therapy for Lymphedema inBreast Cancer Patients PRINCIPAL INVESTIGATOR: Young Kwon Hong, Ph.D. CONTRACTING ORGANIZATION...5a. CONTRACT NUMBER 4. TITLE AND SUBTITLE Lymphatic Reprogramming of Adult Endothelial Stem Cells for a Cell-Based Therapy for Lymphedema in... lymphedema patients. The key significance of our proposal is to utilize the elusive circulating adult stem cells to avoid the ethical and immunological

  1. Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death.

    PubMed

    Garcia-Lavandeira, Montserrat; Diaz-Rodriguez, Esther; Bahar, Dilek; Garcia-Rendueles, Angela R; Rodrigues, Joana S; Dieguez, Carlos; Alvarez, Clara V

    2015-01-01

    The recent demonstration using genetic tracing that in the adult pituitary stem cells are normally recruited from the niche in the marginal zone and differentiate into secretory cells in the adenopituitary has elegantly confirmed the proposal made when the pituitary stem cell niche was first discovered 5 years ago. Some of the early controversies have also been resolved. However, many questions remain, such as which are the markers that make a pituitary stem cell truly unique and the exact mechanisms that trigger recruitment from the niche. Little is known about the processes of commitment and differentiation once a stem cell has left the niche. Moreover, the acceptance that pituitary cells are renewed by stem cells implies the existence of regulated mechanisms of cell death in differentiated cells which must themselves be explained. The demonstration of an apoptotic pathway mediated by RET/caspase 3/Pit-1/Arf/p53 in normal somatotrophs is therefore an important step towards understanding how pituitary cell number is regulated. Further work will elucidate how the rates of the three processes of cell renewal, differentiation and apoptosis are balanced in tissue homeostasis after birth, but altered in pituitary hyperplasia in response to physiological stimuli such as puberty and lactation. Thus, we can aim to understand the mechanisms underlying human disease due to insufficient (hypopituitarism) or excess (pituitary tumor) cell numbers.

  2. Potential for a pluripotent adult stem cell treatment for acute radiation sickness

    PubMed Central

    Rodgerson, Denis O; Reidenberg, Bruce E; Harris, Alan G; Pecora, Andrew L

    2012-01-01

    Accidental radiation exposure and the threat of deliberate radiation exposure have been in the news and are a public health concern. Experience with acute radiation sickness has been gathered from atomic blast survivors of Hiroshima and Nagasaki and from civilian nuclear accidents as well as experience gained during the development of radiation therapy for cancer. This paper reviews the medical treatment reports relevant to acute radiation sickness among the survivors of atomic weapons at Hiroshima and Nagasaki, among the victims of Chernobyl, and the two cases described so far from the Fukushima Dai-Ichi disaster. The data supporting the use of hematopoietic stem cell transplantation and the new efforts to expand stem cell populations ex vivo for infusion to treat bone marrow failure are reviewed. Hematopoietic stem cells derived from bone marrow or blood have a broad ability to repair and replace radiation induced damaged blood and immune cell production and may promote blood vessel formation and tissue repair. Additionally, a constituent of bone marrow-derived, adult pluripotent stem cells, very small embryonic like stem cells, are highly resistant to ionizing radiation and appear capable of regenerating radiation damaged tissue including skin, gut and lung. PMID:24520532

  3. Loss of DNA mismatch repair imparts a selective advantage in planarian adult stem cells.

    PubMed

    Hollenbach, Jessica P; Resch, Alissa M; Palakodeti, Dasaradhi; Graveley, Brenton R; Heinen, Christopher D

    2011-01-01

    Lynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, we utilized the planarian Schmidtea mediterranea which contains a significant population of identifiable adult stem cells. We identified a planarian homolog of human MSH2, a MMR gene which is mutated in 38% of LS cases. The planarian Smed-msh2 is expressed in stem cells and some progeny. We depleted Smed-msh2 mRNA levels by RNA-interference and found a striking survival advantage in these animals treated with a cytotoxic DNA alkylating agent compared to control animals. We demonstrated that this tolerance to DNA damage is due to the survival of mitotically active, MMR-deficient stem cells. Our results suggest that loss of MMR provides an in vivo survival advantage to the stem cell population in the presence of DNA damage that may have implications for tumorigenesis.

  4. The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila.

    PubMed

    Singh, Shree Ram; Zeng, Xiankun; Zhao, Jiangsha; Liu, Ying; Hou, Gerald; Liu, Hanhan; Hou, Steven X

    2016-10-06

    Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients. In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)-Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells. The dying stem cells were engulfed by neighbouring differentiated cells through a draper-myoblast city-Rac1-basket (also known as JNK)-dependent autophagy pathway. Furthermore, Arf1 inhibitors reduced CSCs in human cancer cell lines. Thus, normal or cancer stem cells may rely primarily on lipid reserves for energy, in such a way that blocking lipolysis starves them to death. This finding may lead to new therapies that could help to eliminate CSCs in human cancers.

  5. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division.

    PubMed

    Rocheteau, Pierre; Gayraud-Morel, Barbara; Siegl-Cachedenier, Irene; Blasco, Maria A; Tajbakhsh, Shahragim

    2012-01-20

    Satellite cells are adult skeletal muscle stem cells that are quiescent and constitute a poorly defined heterogeneous population. Using transgenic Tg:Pax7-nGFP mice, we show that Pax7-nGFP(Hi) cells are less primed for commitment and have a lower metabolic status and delayed first mitosis compared to Pax7-nGFP(Lo) cells. Pax7-nGFP(Hi) can give rise to Pax7-nGFP(Lo) cells after serial transplantations. Proliferating Pax7-nGFP(Hi) cells exhibit lower metabolic activity, and the majority performs asymmetric DNA segregation during cell division, wherein daughter cells retaining template DNA strands express stem cell markers. Using chromosome orientation-fluorescence in situ hybridization, we demonstrate that all chromatids segregate asymmetrically, whereas Pax7-nGFP(Lo) cells perform random DNA segregation. Therefore, quiescent Pax7-nGFP(Hi) cells represent a reversible dormant stem cell state, and during muscle regeneration, Pax7-nGFP(Hi) cells generate distinct daughter cell fates by asymmetrically segregating template DNA strands to the stem cell. These findings provide major insights into the biology of stem cells that segregate DNA asymmetrically.

  6. In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain

    PubMed Central

    Fallon, James; Reid, Steve; Kinyamu, Richard; Opole, Isaac; Opole, Rebecca; Baratta, Janie; Korc, Murray; Endo, Tiffany L.; Duong, Alexander; Nguyen, Gemi; Karkehabadhi, Masoud; Twardzik, Daniel; Loughlin, Sandra

    2000-01-01

    The development of an in vivo procedure for the induction of massive proliferation, directed migration, and neurodifferentiation (PMD) in the damaged adult central nervous system would hold promise for the treatment of human neurodegenerative disorders such as Parkinson's disease. We investigated the in vivo induction of PMD in the forebrain of the adult rat by using a combination of 6-hydroxydopamine lesion of the substantia nigra dopaminergic neurons and infusions of transforming growth factor α (TGFα) into forebrain structures. Only in animals with both lesion and infusion of TGFα was there a rapid proliferation of forebrain stem cells followed by a timed migration of a ridge of neuronal and glial progenitors directed toward the region of the TGFα infusion site. Subsequently, increasing numbers of differentiated neurons were observed in the striatum. In behavioral experiments, there was a significant reduction of apomorphine-induced rotations in animals receiving the TGFα infusions. These results show that the brain contains stem cells capable of PMD in response to an exogenously administered growth factor. This finding has significant implications with respect to the development of treatments for both acute neural trauma and neurodegenerative diseases. PMID:11121069

  7. Transplantation of Adult Monkey Neural Stem Cells into A Contusion Spinal Cord Injury Model in Rhesus Macaque Monkeys

    PubMed Central

    Hajinasrollah, Mostafa; Zare Mehrjerdi, Nargess; Azizi, Hossein; Hemmesi, Katayoun; Moghiminasr, Reza; Azhdari, Zahra; Talebi, Ardeshir; Mohitmafi, Soroush; Vosough Taqi Dizaj, Ahmad; Sharifi, Giuve; Baharvand, Hossein; Rezaee, Omidvar; Kiani, Sahar

    2014-01-01

    Objective Currently, cellular transplantation for spinal cord injuries (SCI) is the subject of numerous preclinical studies. Among the many cell types in the adult brain, there is a unique subpopulation of neural stem cells (NSC) that can self-renew and differentiate into neurons. The study aims, therefore, to explore the efficacy of adult monkey NSC (mNSC) in a primate SCI model. Materials and Methods In this experimental study, isolated mNSCs were analyzed by flow cytometry, immunocytochemistry, and RT-PCR. Next, BrdU-labeled cells were transplanted into a SCI model. The SCI animal model was confirmed by magnetic resonance imaging (MRI) and histological analysis. Animals were clinically observed for 6 months. Results Analysis confirmed homing of mNSCs into the injury site. Transplanted cells expressed neuronal markers (TubIII). Hind limb performance improved in trans- planted animals based on Tarlov’s scale and our established behavioral tests for monkeys. Conclusion Our findings have indicated that mNSCs can facilitate recovery in contusion SCI models in rhesus macaque monkeys. Additional studies are necessary to determine the im- provement mechanisms after cell transplantation. PMID:24567941

  8. The Social Environment and Neurogenesis in the Adult Mammalian Brain

    PubMed Central

    Lieberwirth, Claudia; Wang, Zuoxin

    2012-01-01

    Adult neurogenesis – the formation of new neurons in adulthood – has been shown to be modulated by a variety of endogenous (e.g., trophic factors, neurotransmitters, and hormones) as well as exogenous (e.g., physical activity and environmental complexity) factors. Research on exogenous regulators of adult neurogenesis has focused primarily on the non-social environment. More recently, however, evidence has emerged suggesting that the social environment can also affect adult neurogenesis. The present review details the effects of adult–adult (e.g., mating and chemosensory interactions) and adult–offspring (e.g., gestation, parenthood, and exposure to offspring) interactions on adult neurogenesis. In addition, the effects of a stressful social environment (e.g., lack of social support and dominant–subordinate interactions) on adult neurogenesis are reviewed. The underlying hormonal mechanisms and potential functional significance of adult-generated neurons in mediating social behaviors are also discussed. PMID:22586385

  9. Ependymal cells of chordate larvae are stem-like cells that form the adult nervous system.

    PubMed

    Horie, Takeo; Shinki, Ryoko; Ogura, Yosuke; Kusakabe, Takehiro G; Satoh, Nori; Sasakura, Yasunori

    2011-01-27

    In ascidian tunicates, the metamorphic transition from larva to adult is accompanied by dynamic changes in the body plan. For instance, the central nervous system (CNS) is subjected to extensive rearrangement because its regulating larval organs are lost and new adult organs are created. To understand how the adult CNS is reconstructed, we traced the fate of larval CNS cells during ascidian metamorphosis by using transgenic animals and imaging technologies with photoconvertible fluorescent proteins. Here we show that most parts of the ascidian larval CNS, except for the tail nerve cord, are maintained during metamorphosis and recruited to form the adult CNS. We also show that most of the larval neurons disappear and only a subset of cholinergic motor neurons and glutamatergic neurons are retained. Finally, we demonstrate that ependymal cells of the larval CNS contribute to the construction of the adult CNS and that some differentiate into neurons in the adult CNS. An unexpected role of ependymal cells highlighted by this study is that they serve as neural stem-like cells to reconstruct the adult nervous network during chordate metamorphosis. Consequently, the plasticity of non-neuronal ependymal cells and neuronal cells in chordates should be re-examined by future studies.

  10. An update on stem cell biology and engineering for brain development.

    PubMed

    Parr, C J C; Yamanaka, S; Saito, H

    2017-04-04

    Two recent technologies, induced-pluripotent stem cells (iPSCs) and direct somatic reprogramming, have shown enormous potential for cell-based therapies against intractable diseases such as those that affect the central nervous system. Already, methods that generate most major cell types of the human brain exist. Whether the cell types are directly reprogrammed from human somatic cells or differentiated from an iPSC intermediate, the overview presented here demonstrates how these protocols vary greatly in their efficiencies, purity and maturation of the resulting cells. Possible solutions including micro-RNA switch technologies that purify target cell types are also outlined. Further, an update on the transition from 2D to 3D cultures and current organoid (mini-brain) cultures are reviewed to give the stem cell and developmental engineering communities an up-to-date account of the progress and future perspectives for modeling of central nervous system disease and brain development in vitro.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.66.

  11. Galectin-1-secreting neural stem cells elicit long-term neuroprotection against ischemic brain injury

    PubMed Central

    Wang, Jiayin; Xia, Jinchao; Zhang, Feng; Shi, Yejie; Wu, Yun; Pu, Hongjian; Liou, Anthony K. F.; Leak, Rehana K.; Yu, Xinguang; Chen, Ling; Chen, Jun

    2015-01-01

    Galectin-1 (gal-1), a special lectin with high affinity to β-galactosides, is implicated in protection against ischemic brain injury. The present study investigated transplantation of gal-1-secreting neural stem cell (s-NSC) into ischemic brains and identified the mechanisms underlying protection. To accomplish this goal, secretory gal-1 was stably overexpressed in NE-4C neural stem cells. Transient cerebral ischemia was induced in mice by middle cerebral artery occlusion for 60 minutes and s-NSCs were injected into the striatum and cortex within 2 hours post-ischemia. Brain infarct volume and neurological performance were assessed up to 28 days post-ischemia. s-NSC transplantation reduced infarct volume, improved sensorimotor and cognitive functions, and provided more robust neuroprotection than non-engineered NSCs or gal-1-overexpressing (but non-secreting) NSCs. White matter injury was also ameliorated in s-NSC-treated stroke mice. Gal-1 modulated microglial function in vitro, by attenuating secretion of pro-inflammatory cytokines (TNF-α and nitric oxide) in response to LPS stimulation and enhancing production of anti-inflammatory cytokines (IL-10 and TGF-β). Gal-1 also shifted microglia/macrophage polarization toward the beneficial M2 phenotype in vivo by reducing CD16 expression and increasing CD206 expression. In sum, s-NSC transplantation confers robust neuroprotection against cerebral ischemia, probably by alleviating white matter injury and modulating microglial/macrophage function. PMID:25858671

  12. 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.

  13. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

    PubMed Central

    Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

    2016-01-01

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  14. Stemming the Impact of Health Professional Brain Drain from Africa: A Systemic Review of Policy Options

    PubMed Central

    2013-01-01

    Africa has been losing professionally trained health workers who are the core of the health system of this continent for many years. Faced with an increased burden of disease and coupled by a massive exodus of the health workforce, the health systems of many African nations are risking complete paralysis. Several studies have suggested policy options to reduce brain drain from Africa. The purpose of this paper is to review possible policies, which can stem the impact of health professional brain drain from Africa. A systemic literature review was conducted. Cinahl, Science Direct and PubMed databases were searched with the following terms: health professional brain drain from Africa and policies for reducing impact of brain drain from Africa. References were also browsed for relevant articles. A total of 425 articles were available for the study but only 23 articles met the inclusion criteria. The review identified nine policy options, which were being implemented in Africa, but the most common was task shifting which had success in several African countries. This review has demonstrated that there is considerable consensus on task shifting as the most appropriate and sustainable policy option for reducing the impact of health professional brain drain from Africa.

  15. High neuronal/astroglial differentiation plasticity of adult rat hippocampal neural stem/progenitor cells in response to the effects of embryonic and adult cerebrospinal fluids

    PubMed Central

    Peirouvi, T.; Yekani, F.; Azarnia, M.; Massumi, M.

    2015-01-01

    Hippocampal neural stem/progenitor cells (hipp-NS/PCs) of the adult mammalian brain are important sources of neuronal and gial cell production. In this study, the main goal is to investigate the plasticity of these cells in neuronal/astroglial differentiations. To this end, the differentiation of the hipp-NS/PCs isolated from 3-month-old Wistar rats was investigated in response to the embryonic cerebrospinal fluid (E-CSF) including E13.5, E17-CSF and the adult cerebrospinal fluid (A-CSF), all extracted from rats. CSF samples were selected based on their effects on cell behavioral parameters. Primary cell culture was performed in the presence of either normal or high levels of KCL in a culture medium. High levels of KCL cause cell depolarization, and thus the activation of quiescent NSCs. Results from immunocytochemistry (ICC) and semi-quantitative RT-PCR (sRT-PCR) techniques showed that in E-CSF-treated groups, neuronal differentiation increased (E17>E13.5). In contrast, A-CSF decreased and increased neuronal and astroglial differentiations, respectively. Cell survivability and/or proliferation (S/P), evaluated by an MTT assay, increased by E13.5 CSF, but decreased by both E17 CSF and A-CSF. Based on the results, it is finally concluded that adult rat hippocampal proliferative cells are not restricted progenitors but rather show high plasticity in neuronal/astroglial differentiation according to the effects of CSF samples. In addition, using high concentrations of KCL in the primary cell culture led to an increase in the number of NSCs, which in turn resulted in the increase in neuronal or astroglial differentiations after CSF treatment. PMID:27175157

  16. Efficient regeneration by activation of neurogenesis in homeostatically quiescent regions of the adult vertebrate brain.

    PubMed

    Berg, Daniel A; Kirkham, Matthew; Beljajeva, Anna; Knapp, Dunja; Habermann, Bianca; Ryge, Jesper; Tanaka, Elly M; Simon, András

    2010-12-01

    In contrast to mammals, salamanders and teleost fishes can efficiently repair the adult brain. It has been hypothesised that constitutively active neurogenic niches are a prerequisite for extensive neuronal regeneration capacity. Here, we show that the highly regenerative salamander, the red spotted newt, displays an unexpectedly similar distribution of active germinal niches with mammals under normal physiological conditions. Proliferation zones in the adult newt brain are restricted to the forebrain, whereas all other regions are essentially quiescent. However, ablation of midbrain dopamine neurons in newts induced ependymoglia cells in the normally quiescent midbrain to proliferate and to undertake full dopamine neuron regeneration. Using oligonucleotide microarrays, we have catalogued a set of differentially expressed genes in these activated ependymoglia cells. This strategy identified hedgehog signalling as a key component of adult dopamine neuron regeneration. These data show that brain regeneration can occur by activation of neurogenesis in quiescent brain regions.

  17. Differential Responses of Human Fetal Brain Neural Stem Cells to Zika Virus Infection.

    PubMed

    McGrath, Erica L; Rossi, Shannan L; Gao, Junling; Widen, Steven G; Grant, Auston C; Dunn, Tiffany J; Azar, Sasha R; Roundy, Christopher M; Xiong, Ying; Prusak, Deborah J; Loucas, Bradford D; Wood, Thomas G; Yu, Yongjia; Fernández-Salas, Ildefonso; Weaver, Scott C; Vasilakis, Nikos; Wu, Ping

    2017-03-14

    Zika virus (ZIKV) infection causes microcephaly in a subset of infants born to infected pregnant mothers. It is unknown whether human individual differences contribute to differential susceptibility of ZIKV-related neuropathology. Here, we use an Asian-lineage ZIKV strain, isolated from the 2015 Mexican outbreak (Mex1-7), to infect primary human neural stem cells (hNSCs) originally derived from three individual fetal brains. All three strains of hNSCs exhibited similar rates of Mex1-7 infection and reduced proliferation. However, Mex1-7 decreased neuronal differentiation in only two of the three stem cell strains. Correspondingly, ZIKA-mediated transcriptome alterations were similar in these two strains but significantly different from that of the third strain with no ZIKV-induced neuronal reduction. This study thus confirms that an Asian-lineage ZIKV strain infects primary hNSCs and demonstrates a cell-strain-dependent response of hNSCs to ZIKV infection.

  18. Age-Related Differences in the Brain Areas outside the Classical Language Areas among Adults Using Category Decision Task

    ERIC Educational Resources Information Center

    Cho, Yong Won; Song, Hui-Jin; Lee, Jae Jun; Lee, Joo Hwa; Lee, Hui Joong; Yi, Sang Doe; Chang, Hyuk Won; Berl, Madison M.; Gaillard, William D.; Chang, Yongmin

    2012-01-01

    Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that…

  19. Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility.

    PubMed

    Coleman, Leon Garland; Liu, Wen; Oguz, Ipek; Styner, Martin; Crews, Fulton T

    2014-01-01

    Adolescents binge drink more than any other age group, increasing risk of disrupting the development of the frontal cortex. We hypothesized that adolescent binge drinking would lead to persistent alterations in adulthood. In this study, we modeled adolescent weekend underage binge-drinking, using adolescent mice (post-natal days [P] 28-37). The adolescent intermittent binge ethanol (AIE) treatment includes 6 binge intragastric doses of ethanol in an intermittent pattern across adolescence. Assessments were conducted in adulthood following extended abstinence to determine if there were persistent changes in adults. Reversal learning, open field and other behavioral assessments as well as brain structure using magnetic imaging and immunohistochemistry were determined. We found that AIE did not impact adult Barnes Maze learning. However, AIE did cause reversal learning deficits in adults. AIE also caused structural changes in the adult brain. AIE was associated with adulthood volume enlargements in specific brain regions without changes in total brain volume. Enlarged regions included the orbitofrontal cortex (OFC, 4%), cerebellum (4.5%), thalamus (2%), internal capsule (10%) and genu of the corpus callosum (7%). The enlarged OFC volume in adults after AIE is consistent with previous imaging studies in human adolescents. AIE treatment was associated with significant increases in the expression of several extracellular matrix (ECM) proteins in the adult OFC including WFA (55%), Brevican (32%), Neurocan (105%), Tenacin-C (25%), and HABP (5%). These findings are consistent with AIE causing persistent changes in brain structure that could contribute to a lack of behavioral flexibility.

  20. Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility

    PubMed Central

    Coleman, Leon Garland; Liu, Wen; Oguz, Ipek; Styner, Martin; Crews, Fulton T.

    2014-01-01

    Adolescents binge drink more than any other age group, increasing risk of disrupting the development of the frontal cortex. We hypothesized that adolescent binge drinking would lead to persistent alterations in adulthood. In this study, we modeled adolescent weekend underage binge-drinking, using adolescent mice (post-natal days [P] 28–37). The adolescent intermittent binge ethanol (AIE) treatment includes 6 binge intragastric doses of ethanol in an intermittent pattern across adolescence. Assessments were conducted in adulthood following extended abstinence to determine if there were persistent changes in adults. Reversal learning, open field and other behavioral assessments as well as brain structure using magnetic imaging and immunohistochemistry were determined. We found AIE did not impact adult Barnes Maze learning. However, AIE did cause reversal learning deficits in adults. AIE also caused structural changes in the adult brain. AIE was associated with adulthood volume enlargements in specific brain regions without changes in total brain volume. Enlarged regions included the orbitofrontal cortex (OFC, 4%), cerebellum (4.5%), thalamus (2%), internal capsule (10%) and genu of the corpus callosum (7%). The enlarged OFC volume in adults after AIE is consistent with previous imaging studies in human adolescents. AIE treatment was associated with significant increases in the expression of several extracellular matrix (ECM) proteins in the adult OFC including WFA (55%), Brevican (32%), Neurocan (105%), Tenacin-C (25%), and HABP (5%). These findings are consistent with AIE causing persistent changes in brain structure that could contribute to a lack of behavioral flexibility. PMID:24275185

  1. PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.

    PubMed

    Henriksson, Richard; Bäckman, Cristina M; Harvey, Brandon K; Kadyrova, Helena; Bazov, Igor; Shippenberg, Toni S; Bakalkin, Georgy

    2014-11-01

    The dynorphin κ-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  2. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland.

    PubMed

    Pyczek, Joanna; Buslei, Rolf; Schult, David; Hölsken, Annett; Buchfelder, Michael; Heß, Ina; Hahn, Heidi; Uhmann, Anja

    2016-04-25

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2(+) and Sox9(+) adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors.

  3. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland

    PubMed Central

    Pyczek, Joanna; Buslei, Rolf; Schult, David; Hölsken, Annett; Buchfelder, Michael; Heß, Ina; Hahn, Heidi; Uhmann, Anja

    2016-01-01

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2+ and Sox9+ adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors. PMID:27109116

  4. Postnatal stem/progenitor cells derived from the dental pulp of adult chimpanzee

    PubMed Central

    Cheng, Pei-Hsun; Snyder, Brooke; Fillos, Dimitri; Ibegbu, Chris C; Huang, Anderson Hsien-Cheng; Chan, Anthony WS

    2008-01-01

    Background Chimpanzee dental pulp stem/stromal cells (ChDPSCs) are very similar to human bone marrow derived mesenchymal stem/stromal cells (hBMSCs) as demonstrated by the expression pattern of cell surface markers and their multipotent differentiation capability. Results ChDPSCs were isolated from an incisor and a canine of a forty-seven year old female chimpanzee. A homogenous population of ChDPSCs was established in early culture at a high proliferation rate and verified by the expression pattern of thirteen cell surface markers. The ChDPSCs are multipotent and were capable of differentiating into osteogenic, adipogenic and chondrogenic lineages under appropriate in vitro culture conditions. ChDPSCs also express stem cell (Sox-2, Nanog, Rex-1, Oct-4) and osteogenic (Osteonectin, osteocalcin, osteopontin) markers, which is comparable to reported results of rhesus monkey BMSCs (rBMSCs), hBMSCs and hDPSCs. Although ChDPSCs vigorously proliferated during the initial phase and gradually decreased in subsequent passages, the telomere length indicated that telomerase activity was not significantly reduced. Conclusion These results demonstrate that ChDPSCs can be efficiently isolated from post-mortem teeth of adult chimpanzees and are multipotent. Due to the almost identical genome composition of humans and chimpanzees, there is an emergent need for defining the new role of chimpanzee modeling in comparative medicine. Teeth are easy to recover at necropsy and easy to preserve prior to the retrieval of dental pulp for stem/stromal cells isolation. Therefore, the establishment of ChDPSCs would preserve and maximize the applications of such a unique and invaluable animal model, and could advance the understanding of cellular functions and differentiation control of adult stem cells in higher primates. PMID:18430234

  5. Dosimetric analysis of trigeminal nerve, brain stem doses in CyberKnife radiosurgery of trigeminal neuralgia.

    PubMed

    Sudahar, H; Kurup, P G G; Murali, V; Velmurugan, J

    2012-07-01

    CyberKnife radiosurgery treatment of Trigeminal neuralgia (TN) is performed as a non-invasive image guided procedure. The prescription dose for TN is very high. The brainstem is the adjacent critical organ at risk (OAR) which is prone to receive the very high target dose of TN. The present study is to analyze the dose distribution inside the tiny trigeminal nerve target and also to analyze the dose fall off in the brain stem. Seven TN cases treated between November 2010 and January 2012 were taken for this study retrospectively. The treatment plans were analyzed for target dose conformity, homogeneity and dose coverage. In the brainstem the volume doses D(1%), D(2%) were taken for analyzing the higher doses in the brain stem. The dose fall off was analyzed in terms of D(5%) and D(10%). The mean value of maximum dose within the trigeminal nerve target was 73.5±2.1Gy (P=0.0007) and the minimum dose was 50.0±4.1Gy (P=0.1315). The mean conformity index was 2.19 and the probable reason could be the smallest CyberKnife collimator of 5mm used in the treatment plan. The mean D(1%), of the brainstem was 10.5± 2.1Gy (P=0.5316) and the mean value of the maximum point dose within the brainstem was 35.6±3.8Gy. This shows the degree of dose fall off within the brainstem. Though the results of the present study are showing superior sparing of brain stem and reasonable of target coverage, it is necessary to execute the treatment plan with greater accuracy in CyberKnife as the immobilization is noninvasive and frameless.

  6. Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI.

    PubMed

    Jubault, Thomas; Brambati, Simona M; Degroot, Clotilde; Kullmann, Benoît; Strafella, Antonio P; Lafontaine, Anne-Louise; Chouinard, Sylvain; Monchi, Oury

    2009-12-10

    Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders.

  7. Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI

    PubMed Central

    Jubault, Thomas; Brambati, Simona M.; Degroot, Clotilde; Kullmann, Benoît; Strafella, Antonio P.; Lafontaine, Anne-Louise; Chouinard, Sylvain; Monchi, Oury

    2009-01-01

    Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders. PMID:20011063

  8. 660 nm red light-enhanced bone marrow mesenchymal stem cell transplantation for hypoxic-ischemic brain damage treatment.

    PubMed

    Li, Xianchao; Hou, Wensheng; Wu, Xiaoying; Jiang, Wei; Chen, Haiyan; Xiao, Nong; Zhou, Ping

    2014-02-01

    Bone marrow mesenchymal stem cell transplantation is an effective treatment for neonatal hypoxic-ischemic brain damage. However, the in vivo transplantation effects are poor and their survival, colonization and differentiation efficiencies are relatively low. Red or near-infrared light from 600-1,000 nm promotes cellular migration and prevents apoptosis. Thus, we hypothesized that the combination of red light with bone marrow mesenchymal stem cell transplantation would be effective for the treatment of hypoxic-ischemic brain damage. In this study, the migration and colonization of cultured bone marrow mesenchymal stem cells on primary neurons after oxygen-glucose deprivation were detected using Transwell assay. The results showed that, after a 40-hour irradiation under red light-emitting diodes at 660 nm and 60 mW/cm(2), an increasing number of green fluorescence-labeled bone marrow mesenchymal stem cells migrated towards hypoxic-ischemic damaged primary neurons. Meanwhile, neonatal rats with hypoxic-ischemic brain damage were given an intraperitoneal injection of 1 × 10(6) bone marrow mesenchymal stem cells, followed by irradiation under red light-emitting diodes at 660 nm and 60 mW/cm(2) for 7 successive days. Shuttle box test results showed that, after phototherapy and bone marrow mesenchymal stem cell transplantation, the active avoidance response rate of hypoxic-ischemic brain damage rats was significantly increased, which was higher than that after bone marrow mesenchymal stem cell transplantation alone. Experimental findings indicate that 660 nm red light emitting diode irradiation promotes the migration of bone marrow mesenchymal stem cells, thereby enhancing the contribution of cell transplantation in the treatment of hypoxic-ischemic brain damage.

  9. Simultaneous control of stemness and differentiation by the transcription factor Escargot in adult stem cells: How can we tease them apart?

    PubMed Central

    Loza-Coll, Mariano A.; Jones, D. Leanne

    2016-01-01

    ABSTRACT The homeostatic turnover of adult organs and their regenerative capacity following injury depend on a careful balance between stem cell self-renewal (to maintain or enlarge the stem cell pool) and differentiation (to replace lost tissue). We have recently characterized the role of the Drosophila Snail family transcription factor escargot (esg) in testis cyst stem cells (CySCs)1,2 and intestinal stem cells (ISCs). 3,4 CySCs mutant for esg are not maintained as stem cells, but they remain capable of differentiating normally along the cyst cell lineage. In contrast, esg mutant CySCs that give rise to a closely related lineage, the apical hub cells, cannot maintain hub cell identity. Similarly, Esg maintains stemness of ISCs while regulating the terminal differentiation of progenitor cells into absorptive enterocytes or secretory enteroendocrine cells. Therefore, our findings suggest that Esg may play a conserved and pivotal regulatory role in adult stem cells, controlling both their maintenance and terminal differentiation. Here we propose that this dual regulatory role is due to simultaneous control by Esg of overlapping genetic programs and discuss the exciting challenges and opportunities that lie ahead to explore the underlying mechanisms experimentally. PMID:27077690

  10. Hallmarks of Alzheimer's Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain.

    PubMed

    Espuny-Camacho, Ira; Arranz, Amaia M; Fiers, Mark; Snellinx, An; Ando, Kunie; Munck, Sebastian; Bonnefont, Jerome; Lambot, Laurie; Corthout, Nikky; Omodho, Lorna; Vanden Eynden, Elke; Radaelli, Enrico; Tesseur, Ina; Wray, Selina; Ebneth, Andreas; Hardy, John; Leroy, Karelle; Brion, Jean-Pierre; Vanderhaeghen, Pierre; De Strooper, Bart

    2017-03-08

    Human pluripotent stem cells (PSCs) provide a unique entry to study species-specific aspects of human disorders such as Alzheimer's disease (AD). However, in vitro culture of neurons deprives them of their natural environment. Here we transplanted human PSC-derived cortical neuronal precursors into the brain of a murine AD model. Human neurons differentiate and integrate into the brain, express 3R/4R Tau splice forms, show abnormal phosphorylation and conformational Tau changes, and undergo neurodegeneration. Remarkably, cell death was dissociated from tangle formation in this natural 3D model of AD. Using genome-wide expression analysis, we observed upregulation of genes involved in myelination and downregulation of genes related to memory and cognition, synaptic transmission, and neuron projection. This novel chimeric model for AD displays human-specific pathological features and allows the analysis of different genetic backgrounds and mutations during the course of the disease.

  11. [A case of chronic aspiration pneumonia caused by juvenile brain stem tumor].

    PubMed

    Miyagawa, Tomoko; Mochizuki, Yoshirou; Nakahara, Yasuharu; Kawamura, Tetsuji; Sasaki, Shin; Tsukamoto, Hiroaki; Tabata, Hisako; Okada, Hideaki; Kobashi, Youichirou

    2009-03-01

    A 23-year-old man had been treated for repeated pneumonia from the age of 16. After a diagnosis of eosinophilic pneumonia at the age of 17, he had been given antibiotics and steroids. At the age of 23, he was referred to our hospital. Although he improved rapidly in response to antibiotic medication, his chest X-ray shadows did not improve. Video-assisted thoracoscopic lung biopsy was performed. Fibrosis and invasion of inflammatory cells were seen on the air duct walls and foreign bodies that were thought to be food residue were detected. A diagnosis of chronic aspiration pneumonia was made pathologically. A brain stem tumor was detected on his brain magnetic resonance imaging, which was thought to be the cause of his mis-swallowing.

  12. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation

    PubMed Central

    Liu, Qiang; Sanai, Nader; Jin, Wei-Na; La Cava, Antonio; Van Kaer, Luc; Shi, Fu-Dong

    2017-01-01

    Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair. PMID:26752157

  13. Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina.

    PubMed

    Park, Hae-Young Lopilly; Kim, Jie Hyun; Sun Kim, Hwa; Park, Chan Kee

    2012-08-21

    As an alternative to a viral vector, the application of stem cells to transfer specific genes is under investigation in various organs. Using this strategy may provide more effective method to supply neurotrophic factor to the neurodegenerative diseases caused by neurotrophic factor deprivation. This study investigated the possibility and efficacy of stem cell-based delivery of the brain-derived neurotrophic factor (BDNF) gene to rat retina. Rat BDNF cDNA was transduced into rat bone marrow mesenchymal stem cells (rMSCs) using a retroviral vector. Its incorporation into the experimental rat retina and the expression of BDNF after intravitreal injection or subretinal injection were detected by real-time PCR, western blot analysis, and immunohistochemical staining. For the incorporated rMSCs, retinal-specific marker staining was performed to investigate the changes in morphology and the characteristics of the stem cells. Transduction of the rMSCs by retrovirus was effective, and the transduced rMSCs expressed high levels of the BDNF gene and protein. The subretinal injection of rMSCs produced rMSC migration and incorporation into the rat retina (about 15.7% incorporation rate), and retinal BDNF mRNA and protein expression was increased at 4 weeks after transplantation. When subretinal injection of rMSCs was applied to axotomized rat retina, it significantly increased the expression of BDNF until 4 weeks after transplantation. Some of the transplanted rMSCs exhibited morphological changes, but the retinal-specific marker stain was not sufficient to indicate whether neuronal differentiation had occurred. Using mesenchymal stem cells to deliver the BDNF gene to the retina may provide new treatment for glaucoma.

  14. Isolated Rat Epididymal Basal Cells Share Common Properties with Adult Stem Cells1

    PubMed Central

    Mandon, Marion; Hermo, Louis; Cyr, Daniel G.

    2015-01-01

    There is little information on the function of epididymal basal cells. These cells secrete prostaglandins, can metabolize radical oxygen species, and have apical projections that are components of the blood-epididymis barrier. The objective of this study was to develop a reproducible protocol to isolate rat epididymal basal cells and to characterize their function by gene expression profiling. Integrin-alpha6 was used to isolate a highly purified population of basal cells. Microarray analysis indicated that expression levels of 552 genes were enriched in basal cells relative to other cell types. Among these genes, 45 were expressed at levels of 5-fold or greater. These highly expressed genes coded for proteins implicated in cell adhesion, cytoskeletal function, ion transport, cellular signaling, and epidermal function, and included proteases and antiproteases, signal transduction, and transcription factors. Several highly expressed genes have been reported in adult stem cells, suggesting that basal cells may represent an epididymal stem cell population. A basal cell culture was established that showed that these basal cells can differentiate in vitro from keratin (KRT) 5-positive cells to cells that express KRT8 and connexin 26, a marker of columnar cells. These data provide novel information on epididymal basal cell gene expression and suggest that these cells can act as adult stem cells. PMID:26400399

  15. Sex, stress and the brain: interactive actions of hormones on the developing and adult brain.

    PubMed

    McEwen, B S

    2014-12-01

    The brain is a target of steroid hormone actions that affect brain architecture, molecular and neurochemical processes, behavior and neuroprotection via both genomic and non-genomic actions. Estrogens have such effects throughout the brain and this article provides an historical and current view of how this new view has come about and how it has affected the study of sex differences, as well as other areas of neuroscience, including the effects of stress on the brain.

  16. BDNF Expression in Larval and Adult Zebrafish Brain: Distribution and Cell Identification

    PubMed Central

    Cacialli, Pietro; Gueguen, Marie-Madeleine; Coumailleau, Pascal; D’Angelo, Livia; Kah, Olivier; Lucini, Carla; Pellegrini, Elisabeth

    2016-01-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has emerged as an active mediator in many essential functions in the central nervous system of mammals. BDNF plays significant roles in neurogenesis, neuronal maturation and/or synaptic plasticity and is involved in cognitive functions such as learning and memory. Despite the vast literature present in mammals, studies devoted to BDNF in the brain of other animal models are scarse. Zebrafish is a teleost fish widely known for developmental genetic studies and is emerging as model for translational neuroscience research. In addition, its brain shows many sites of adult neurogenesis allowing higher regenerative properties after traumatic injuries. To add further knowledge on neurotrophic factors in vertebrate brain models, we decided to determine the distribution of bdnf mRNAs in the larval and adult zebrafish brain and to characterize the phenotype of cells expressing bdnf mRNAs by means of double staining studies. Our results showed that bdnf mRNAs were widely expressed in the brain of 7 days old larvae and throughout the whole brain of mature female and male zebrafish. In adults, bdnf mRNAs were mainly observed in the dorsal telencephalon, preoptic area, dorsal thalamus, posterior tuberculum, hypothalamus, synencephalon, optic tectum and medulla oblongata. By combining immunohistochemistry with in situ hybridization, we showed that bdnf mRNAs were never expressed by radial glial cells or proliferating cells. By contrast, bdnf transcripts were expressed in cells with neuronal phenotype in all brain regions investigated. Our results provide the first demonstration that the brain of zebrafish expresses bdnf mRNAs in neurons and open new fields of research on the role of the BDNF factor in brain mechanisms in normal and brain repairs situations. PMID:27336917

  17. Clonal development and organization of the adult Drosophila central brain

    PubMed Central

    Yu, Hung-Hsiang; Awasaki, Takeshi; Schroeder, Mark David; Long, Fuhui; Yang, Jacob S.; He, Yisheng; Ding, Peng; Kao, Jui-Chun; Wu, Gloria Yueh-Yi; Peng, Hanchuan; Myers, Gene; Lee, Tzumin

    2013-01-01

    Summary Background The insect brain can be divided into neuropils that are formed by neurites of both local and remote origin. The complexity of the interconnections obscures how these neuropils are established and interconnected through development. The Drosophila central brain develops from a fixed number of neuroblasts (NBs) that deposit neurons in regional clusters. Results By determining individual NB clones and pursuing their projections into specific neuropils we unravel the regional development of the brain neural network. Exhaustive clonal analysis revealed 95 stereotyped neuronal lineages with characteristic cell body locations and neurite trajectories. Most clones show complex projection patterns, but despite the complexity, neighboring clones often co-innervate the same local neuropil(s) and further target a restricted set of distant neuropils. Conclusions These observations argue for regional clonal development of both neuropils and neuropil connectivity throughout the Drosophila central brain. PMID:23541733

  18. Utilizing pharmacotherapy and mesenchymal stem cell therapy to reduce inflammation following traumatic brain injury

    PubMed Central

    Mashkouri, Sherwin; Crowley, Marci G.; Liska, Michael G.; Corey, Sydney; Borlongan, Cesar V.

    2016-01-01

    The pathologic process of chronic phase traumatic brain injury is associated with spreading inflammation, cell death, and neural dysfunction. It is thought that sequestration of inflammatory mediators can facilitate recovery and promote an environment that fosters cellular regeneration. Studies have targeted post-traumatic brain injury inflammation with the use of pharmacotherapy and cell therapy. These therapeutic options are aimed at reducing the edematous and neurodegenerative inflammation that have been associated with compromising the integrity of the blood-brain barrier. Although studies have yielded positive results from anti-inflammatory pharmacotherapy and cell therapy individually, emerging research has begun to target inflammation using combination therapy. The joint use of anti-inflammatory drugs alongside stem cell transplantation may provide better clinical outcomes for traumatic brain injury patients. Despite the promising results in this field of research, it is important to note that most of the studies mentioned in this review have completed their studies using animal models. Translation of this research into a clinical setting will require additional laboratory experiments and larger preclinical trials. PMID:27857726

  19. Paving the way towards complex blood-brain barrier models using pluripotent stem cells.

    PubMed

    Lauschke, Karin; Frederiksen, Lise; Hall, Vanessa J

    2017-04-11

    A tissue with great need to be modelled in vitro is the blood-brain barrier (BBB). The BBB is a tight barrier that covers all blood vessels in the brain and separates the brain microenvironment from the blood system. It consists of three cell types (neurovascular unit (NVU)) that contribute to the unique tightness and selective permeability of the BBB and has been shown to be disrupted in many diseases and brain disorders, such as, vascular dementia, stroke, multiple sclerosis and Alzheimer's disease. Given the progress that pluripotent stem cells (PSCs) have made in the last two decades, it is now possible to produce many cell types from the BBB and even partially recapitulate this complex tissue in vitro. In this review, we summarize the most recent developments in PSC differentiation and modelling of the BBB. We also suggest how patient-specific human induced PSCs could be used to model BBB dysfunction in the future. Lastly, we provide perspectives on how to improve production of the BBB in vitro, for example by improving pericyte differentiation protocols and by better modelling the NVU in the dish.

  20. Arthropod phylogeny: onychophoran brain organization suggests an archaic relationship with a chelicerate stem lineage

    PubMed Central

    Strausfeld, Nicholas J; Mok Strausfeld, Camilla; Loesel, Rudi; Rowell, David; Stowe, Sally

    2006-01-01

    Neuroanatomical studies have demonstrated that the architecture and organization among neuropils are highly conserved within any order of arthropods. The shapes of nerve cells and their neuropilar arrangements provide robust characters for phylogenetic analyses. Such analyses so far have agreed with molecular phylogenies in demonstrating that entomostracans+malacostracans belong to a clade (Tetraconata) that includes the hexapods. However, relationships among what are considered to be paraphyletic groups or among the stem arthropods have not yet been satisfactorily resolved. The present parsimony analyses of independent neuroarchitectural characters from 27 arthropods and lobopods demonstrate relationships that are congruent with phylogenies derived from molecular studies, except for the status of the Onychophora. The present account describes the brain of the onychophoran Euperipatoides rowelli, demonstrating that the structure and arrangements of its neurons, cerebral neuropils and sensory centres are distinct from arrangements in the brains of mandibulates. Neuroanatomical evidence suggests that the organization of the onychophoran brain is similar to that of the brains of chelicerates. PMID:16822744

  1. 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.

  2. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain.

    PubMed

    Kawai, Hiromi; Yamashita, Toru; Ohta, Yasuyuki; Deguchi, Kentaro; Nagotani, Shoko; Zhang, Xuemei; Ikeda, Yoshio; Matsuura, Tohru; Abe, Koji

    2010-08-01

    Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5 x 10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

  3. Human Blood-Brain Barrier Endothelial Cells Derived from Pluripotent Stem Cells

    PubMed Central

    Lippmann, Ethan S.; Azarin, Samira M.; Kay, Jennifer E.; Nessler, Randy A.; Wilson, Hannah K.; Al-Ahmad, Abraham; Palecek, Sean P.; Shusta, Eric V.

    2012-01-01

    The blood-brain barrier (BBB) plays an important role in brain health and is often compromised in disease. Moreover, as a result of its significant barrier properties, this endothelial interface restricts neurotherapeutic uptake. Thus, a renewable source of human BBB endothelium could prove enabling for brain research and pharmaceutical development. Herein, we demonstrate that endothelial cells generated from human pluripotent stem cells (hPSCs) can be specified to possess many BBB attributes, including well-organized tight junctions, expression of nutrient transporters, and polarized efflux transporter activity. Importantly, hPSC-derived BBB endothelial cells respond to astrocytic cues yielding impressive barrier properties as measured by transendothelial electrical resistance (1450±140 Ωxcm2) and molecular permeability that correlates well with in vivo brain uptake. In addition, specification of hPSC-derived BBB endothelial cells occurs in concert with neural cell co-differentiation via Wnt/β-catenin signaling, consistent with previous transgenic studies. This study represents the first example of organ-specific endothelial differentiation from hPSCs. PMID:22729031

  4. Injection of SDF-1 loaded nanoparticles following traumatic brain injury stimulates neural stem cell recruitment.

    PubMed

    Zamproni, Laura N; Mundim, Mayara V; Porcionatto, Marimelia A; des Rieux, Anne

    2017-03-15

    Recruiting neural stem cell (NSC) at the lesion site is essential for central nervous system repair. This process could be triggered by the local delivery of the chemokine SDF-1. We compared two PLGA formulations for local brain SDF-1 delivery: SDF-1 loaded microspheres (MS) and SDF-1 loaded nanoparticles (NP). Both formulations were able to encapsulate more than 80% of SDF-1 but presented different release profiles, with 100% of SDF-1 released after 6days for the MS and with 25% of SDF-1 released after 2 weeks for NP. SDF-1 bioactivity was demonstrated by a chemotactic assay. When injected in mouse brain after traumatic brain injury, only SDF-1 nanoparticles induced NSC migration to the damage area. More neuroblasts (DCX+ cells) could be visualized around the lesions treated with NP SDF-1 compared to the other conditions. Rostral migratory stream destabilization with massive migration of DCX+ cell toward the perilesional area was observed 2 weeks after NP SDF-1 injection. Local injection of SDF-1-loaded nanoparticles induces recruitment of NSC and could be promising for brain injury lesion.

  5. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function.

    PubMed

    Middendorp, Sabine; Schneeberger, Kerstin; Wiegerinck, Caroline L; Mokry, Michal; Akkerman, Ronald D L; van Wijngaarden, Simone; Clevers, Hans; Nieuwenhuis, Edward E S

    2014-05-01

    Differentiation and specialization of epithelial cells in the small intestine are regulated in two ways. First, there is differentiation along the crypt-villus axis of the intestinal stem cells into absorptive enterocytes, Paneth, goblet, tuft, enteroendocrine, or M cells, which is mainly regulated by WNT. Second, there is specialization along the cephalocaudal axis with different absorptive and digestive functions in duodenum, jejunum, and ileum that is controlled by several transcription factors such as GATA4. However, so far it is unknown whether location-specific functional properties are intrinsically programmed within stem cells or if continuous signaling from mesenchymal cells is necessary to maintain the location-specific identity of the small intestine. Using the pure epithelial organoid technique, we show that region-specific gene expression profiles are conserved throughout long-term cultures of both mouse and human intestinal stem cells and correlated with differential Gata4 expression. Furthermore, the human organoid culture system demonstrates that Gata4-regulated gene expression is only allowed in absence of WNT signaling. These data show that location-specific function is intrinsically programmed in the adult stem cells of the small intestine and that their differentiation fate is independent of location-specific extracellular signals. In light of the potential future clinical application of small intestine-derived organoids, our data imply that it is important to generate GATA4-positive and GATA4-negative cultures to regenerate all essential functions of the small intestine.

  6. An RbAp48-like gene regulates adult stem cells in planarians.

    PubMed

    Bonuccelli, Lucia; Rossi, Leonardo; Lena, Annalisa; Scarcelli, Vittoria; Rainaldi, Giuseppe; Evangelista, Monica; Iacopetti, Paola; Gremigni, Vittorio; Salvetti, Alessandra

    2010-03-01

    Retinoblastoma-associated proteins 46 and 48 (RbAp46 and RbAp48) are factors that are components of different chromatin-modelling complexes, such as polycomb repressive complex 2, the activity of which is related to epigenetic gene regulation in stem cells. To date, no direct findings are available on the in vivo role of RbAp48 in stem-cell biology. We recently identified DjRbAp48 - a planarian (Dugesia japonica) homologue of human RBAP48 - expression of which is restricted to the neoblasts, the adult stem cells of planarians. In vivo silencing of DjRbAp48 induces lethality and inability to regenerate, even though neoblasts proliferate and accumulate after wounding. Despite a partial reduction in neoblast number, we were always able to detect a significant number of these cells in DjRbAp48 RNAi animals. Parallel to the decrease in neoblasts, a reduction in the number of differentiated cells and the presence of apoptotic-like neoblasts were detectable in RNAi animals. These findings suggest that DjRbAp48 is not involved in neoblast maintenance, but rather in the regulation of differentiation of stem-cell progeny. We discuss our data, taking into account the possibility that DjRbAp48 might control the expression of genes necessary for cell differentiation by influencing chromatin architecture.

  7. Tumorigenic Potential of Olfactory Bulb-Derived Human Adult Neural Stem Cells Associates with Activation of TERT and NOTCH1

    PubMed Central

    Ricci-Vitiani, Lucia; Cenciarelli, Carlo; Petrucci, Giovanna; Milazzo, Luisa; Montano, Nicola; Tabolacci, Elisabetta; Maira, Giulio; Larocca, Luigi M.; Pallini, Roberto

    2009-01-01

    Background Multipotent neural stem cells (NSCs) have been isolated from neurogenic regions of the adult brain. Reportedly, these cells can be expanded in vitro under prolonged mitogen stimulation without propensity to transform. However, the constitutive activation of the cellular machinery required to bypass apoptosis and senescence places these cells at risk for malignant transformation. Methodology/Principal Findings Using serum-free medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), we established clonally derived NS/progenitor cell (NS/PC) cultures from the olfactory bulb (OB) of five adult patients. The NS/PC cultures obtained from one OB specimen lost growth factor dependence and neuronal differentiation at early passage. These cells developed glioblastoma tumors upon xenografting in immunosuppressed mice. The remaining NS/PC cultures were propagated either as floating neurospheres or as adherent monolayers with mainteinance of growth factor dependence and multipotentiality at late passage. These cells were engrafted onto the CNS of immunosuppressed rodents. Overall, the grafted NS/PCs homed in the host parenchyma showing ramified morphology and neuronal marker expression. However, a group of animals transplanted with NS/PCs obtained from an adherent culture developed fast growing tumors histologically resembling neuroesthesioblastoma. Cytogenetic and molecular analyses showed that the NS/PC undergo chromosomal changes with repeated in vitro passages under mitogen stimulation, and that up-regulation of hTERT and NOTCH1 associates with in vivo tumorigenicity. Conclusions/Significance Using culturing techniques described in current literature, NS/PCs arise from the OB of adult patients which in vivo either integrate in the CNS parenchyma showing neuron-like features or initiate tumor formation. Extensive xenografting studies on each human derived NS cell line appear mandatory before any use of these cells in the

  8. 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

  9. Neonatal hypoxic insult-mediated cholinergic disturbances in the brain stem: effect of glucose, oxygen and epinephrine resuscitation.

    PubMed

    Anju, T R; Naijil, G; Shilpa, J; Roshni, T; Paulose, C S

    2013-03-01

    Molecular processes regulating cholinergic functions play an important role in the control of respiration under neonatal hypoxia. The present study evaluates neonatal hypoxic insult-mediated cholinergic alterations and the protective role of glucose, oxygen and epinephrine resuscitation. The changes in total muscarinic, muscarinic M1, M2, M3 receptors and the enzymes involved in acetylcholine metabolism--cholineacetyl transferase and acetylcholine easterase in the brain stem were analyzed. Hypoxic stress decreased total muscarinic receptors along with a reduction in muscarinic M1, M2 and M3 receptor genes in the brain stem. The reduction in acetylcholine metabolism is indicated by the down regulated cholineacetyl transferase and up regulated acetylcholine easterase expression. These cholinergic disturbances in the brain stem were reversed by glucose resuscitation to hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration were also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.

  10. Event-related brain potentials - Comparison between children and adults

    NASA Technical Reports Server (NTRS)

    Courchesne, E.

    1977-01-01

    The reported investigation shows that nontarget stimuli which are infrequently presented and deviate from the background elicit Nc and Pc waves in children. The same stimuli elicit P3 waves in adults. The scalp distribution of P3 waves in adults appears to vary with the ease of stimulus recognition or the degree of stimulus novelty. However, the Nc and Pc distributions in children do not seem to vary with these factors. The differences between children and adults in event-related potentials suggest corresponding differences in the mode of processing employed by each when rare, deviant stimuli are encountered

  11. Morphological brain network assessed using graph theory and network filtration in deaf adults.

    PubMed

    Kim, Eunkyung; Kang, Hyejin; Lee, Hyekyoung; Lee, Hyo-Jeong; Suh, Myung-Whan; Song, Jae-Jin; Oh, Seung-Ha; Lee, Dong Soo

    2014-09-01

    Prolonged deprivation of auditory input can change brain networks in pre- and postlingual deaf adults by brain-wide reorganization. To investigate morphological changes in these brains voxel-based morphometry, voxel-wise correlation with the primary auditory cortex, and whole brain network analyses using morphological covariance were performed in eight prelingual deaf, eleven postlingual deaf, and eleven hearing adults. Network characteristics based on graph theory and network filtration based on persistent homology were examined. Gray matter density in the primary auditor cortex was preserved in prelingual deafness, while it tended to decrease in postlingual deafness. Unlike postlingual, prelingual deafness showed increased bilateral temporal connectivity of the primary auditory cortex compared to the hearing adults. Of the graph theory-based characteristics, clustering coefficient, betweenness centrality, and nodal efficiency all increased in prelingual deafness, while all the parameters of postlingual deafness were similar to the hearing adults. Patterns of connected components changing during network filtration were different between prelingual deafness and hearing adults according to the barcode, dendrogram, and single linkage matrix representations, while these were the same in postlingual deafness. Nodes in fronto-limbic and left temporal components were closely coupled, and nodes in the temporo-parietal component were loosely coupled, in prelingual deafness. Patterns of connected components changing in postlingual deafness were the same as hearing adults. We propose that the preserved density of auditory cortex associated with increased connectivity in prelingual deafness, and closer coupling between certain brain areas, represent distinctive reorganization of auditory and related cortices compared with hearing or postlingual deaf adults. The differential network reorganization in the prelingual deaf adults could be related to the absence of auditory speech

  12. The postnatal origin of adult neural stem cells and the effects of glucocorticoids on their genesis.

    PubMed

    Ortega-Martínez, Sylvia; Trejo, José L

    2015-02-15

    The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety-like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior.

  13. Harnessing the potential of adult cardiac stem cells: lessons from haematopoiesis, the embryo and the niche.

    PubMed

    Balmer, Gemma M; Riley, Paul R

    2012-10-01

    Across biomedicine, there is a major drive to develop stem cell (SC) treatments for debilitating diseases. Most effective treatments restore an embryonic phenotype to adult SCs. This has led to two emerging paradigms in SC biology: the application of developmental biology studies and the manipulation of the SC niche. Developmental studies can reveal how SCs are orchestrated to build organs, the understanding of which is important in order to instigate tissue repair in the adult. SC niche studies can reveal cues that maintain SC 'stemness' and how SCs may be released from the constraints of the niche to differentiate and repopulate a 'failing' organ. The haematopoietic system provides an exemplar whereby characterisation of the blood lineages during development and the bone marrow niche has resulted in therapeutics now routinely used in the clinic. Ischaemic heart disease is a major cause of morbidity and mortality in humans and the question remains as to whether these principles can be applied to the heart, in order to exploit the potential of adult SCs for use in cardiovascular repair and regeneration.

  14. Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy.

    PubMed

    Pittatore, G; Moggio, A; Benedetto, C; Bussolati, B; Revelli, A

    2014-03-01

    The cyclical arrival of endometrial cells into the abdominal cavity through retrograde flux at menstruation represents the etiopathogenetic basis of endometriosis. The endometrium has peculiar regenerative properties linked to the presence of adult stem cells similar to mesenchymal stem cells (MSCs). Once in the abdominal cavity, these MSCs could proliferate, invade, and differentiate into endometrial cells, finally generating ectopic implants. As only differentiated endometrial cells, and not endometrial MSCs, possess steroid hormone receptors, MSCs could be responsible for the high rate of persistence/recurrence of the disease after hypoestrogenism-inducing therapies. Even angiogenesis promoted by MSCs could play an important role, as survival and proliferation of endometriotic tissue depend on the formation of new blood vessels. Inhibition of angiogenesis represents, in fact, a new, promising therapeutic approach for the disease. Further, medications directly targeting endometriosis MSCs could be effective, alone or in association with hormonal treatments, in increasing the success of medical treatment.

  15. Adult stem cells, scaffolds for in vivo and in vitro myocardial tissue engineering.

    PubMed

    Di Felice, Valentina; De Luca, Angela; Serradifalco, Claudia; Di Marco, Patrizia; Verin, Lucia; Motta, Antonella; Guercio, Annalisa; Zummo, Giovanni

    2010-01-01

    The main goal in the last few years in cardiac research has been to isolate cardiac potential stem cells from adult myocardium and to demonstrate their differentiation potential. We have previously demonstrated that c-Kit positive cardiac stem cells are able to organize themselves into a tissue-like cell mass. In this 3D mass, they can produce a high concentration of natural extracellular matrix, can create vessels, a capsule and, with the help of an Open-pore Polylactic Acid scaffold, many cells can organize an elementary myocardium. Drawing from this background, we decided to design and use poly-lactic scaffolds and the model of the athymic Nude-Foxn1(nu) mouse to evaluate the extent of the myogenic vs endothelial differentiation in vivo, and to evaluate the presence or the absence of a foreign body reaction.

  16. Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells

    PubMed Central

    Souilhol, Céline; Gonneau, Christèle; Lendinez, Javier G.; Batsivari, Antoniana; Rybtsov, Stanislav; Wilson, Heather; Morgado-Palacin, Lucia; Hills, David; Taoudi, Samir; Antonchuk, Jennifer; Zhao, Suling; Medvinsky, Alexander

    2016-01-01

    During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta–gonad–mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso–ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs. PMID:26952187

  17. Development and modulation of intrinsic membrane properties control the temporal precision of auditory brain stem neurons.

    PubMed

    Franzen, Delwen L; Gleiss, Sarah A; Berger, Christina; Kümpfbeck, Franziska S; Ammer, Julian J; Felmy, Felix

    2015-01-15

    Passive and active membrane properties determine the voltage responses of neurons. Within the auditory brain stem, refinements in these intrinsic properties during late postnatal development usually generate short integration times and precise action-potential generation. This developmentally acquired temporal precision is crucial for auditory signal processing. How the interactions of these intrinsic properties develop in concert to enable auditory neurons to transfer information with high temporal precision has not yet been elucidated in detail. Here, we show how the developmental interaction of intrinsic membrane parameters generates high firing precision. We performed in vitro recordings from neurons of postnatal days 9-28 in the ventral nucleus of the lateral lemniscus of Mongolian gerbils, an auditory brain stem structure that converts excitatory to inhibitory information with high temporal precision. During this developmental period, the input resistance and capacitance decrease, and action potentials acquire faster kinetics and enhanced precision. Depending on the stimulation time course, the input resistance and capacitance contribute differentially to action-potential thresholds. The decrease in input resistance, however, is sufficient to explain the enhanced action-potential precision. Alterations in passive membrane properties also interact with a developmental change in potassium currents to generate the emergence of the mature firing pattern, characteristic of coincidence-detector neurons. Cholinergic receptor-mediated depolarizations further modulate this intrinsic excitability profile by eliciting changes in the threshold and firing pattern, irrespective of the developmental stage. Thus our findings reveal how intrinsic membrane properties interact developmentally to promote temporally precise information processing.

  18. aBEAT: A Toolbox for Consistent Analysis of Longitudinal Adult Brain MRI

    PubMed Central

    Dai, Yakang; Wang, Yaping; Wang, Li; Wu, Guorong; Shi, Feng; Shen, Dinggang

    2013-01-01

    Longitudinal brain image analysis is critical for revealing subtle but complex structural and functional changes of brain during aging or in neurodevelopmental disease. However, even with the rapid increase of clinical research and trials, a software toolbox dedicated for longitudinal image analysis is still lacking publicly. To cater for this increasing need, we have developed a dedicated 4D Adult Brain Extraction and Analysis Toolbox (aBEAT) to provide robust and accurate analysis of the longitudinal adult brain MR images. Specially, a group of image processing tools were integrated into aBEAT, including 4D brain extraction, 4D tissue segmentation, and 4D brain labeling. First, a 4D deformable-surface-based brain extraction algorithm, which can deform serial brain surfaces simultaneously under temporal smoothness constraint, was developed for consistent brain extraction. Second, a level-sets-based 4D tissue segmentation algorithm that incorporates local intensity distribution, spatial cortical-thickness constraint, and temporal cortical-thickness consistency was also included in aBEAT for consistent brain tissue segmentation. Third, a longitudinal groupwise image registration framework was further integrated into aBEAT for consistent ROI labeling by simultaneously warping a pre-labeled brain atlas to the longitudinal brain images. The performance of aBEAT has been extensively evaluated on a large number of longitudinal MR T1 images which include normal and dementia subjects, achieving very promising results. A Linux-based standalone package of aBEAT is now freely available at http://www.nitrc.org/projects/abeat. PMID:23577105

  19. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

    PubMed

    Luo, Yuping; Shan, Ge; Guo, Weixiang; Smrt, Richard D; Johnson, Eric B; Li, Xuekun; Pfeiffer, Rebecca L; Szulwach, Keith E; Duan, Ranhui; Barkho, Basam Z; Li, Wendi; Liu, Changmei; Jin, Peng; Zhao, Xinyu

    2010-04-08

    Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.

  20. Multipotent stem cells isolated from the adult mouse retina are capable of producing functional photoreceptor cells.

    PubMed

    Li, Tianqing; Lewallen, Michelle; Chen, Shuyi; Yu, Wei; Zhang, Nian; Xie, Ting

    2013-06-01

    Various stem cell types have been tested for their potential application in treating photoreceptor degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Only embryonic stem cells (ESCs) have so far been shown to generate functional photoreceptor cells restoring light response of photoreceptor-deficient mice, but there is still some concern of tumor formation. In this study, we have successfully cultured Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells (RSCs) from the adult mouse retina, which are capable of producing functional photoreceptor cells that restore the light response of photoreceptor-deficient rd1 mutant mice following transplantation. After they have been expanded for over 35 passages in the presence of FGF and EGF, the cultured RSCs still maintain stable proliferation and differentiation potential. Under proper differentiation conditions, they can differentiate into all the major retinal cell types found in the adult retina. More importantly, they can efficiently differentiate into photoreceptor cells under optimized differentiation conditions. Following transplantation into the subretinal space of slowly degenerating rd7 mutant eyes, RSC-derived photoreceptor cells integrate into the retina, morphologically resembling endogenous photoreceptors and forming synapases with resident retinal neurons. When transplanted into eyes of photoreceptor-deficient rd1 mutant mice, a RP model, RSC-derived photoreceptors can partially restore light response, indicating that those RSC-derived photoreceptors are functional. Finally, there is no evidence for tumor formation in the photoreceptor-transplanted eyes. Therefore, this study has demonstrated that RSCs isolated from the adult retina have the potential of producing functional photoreceptor cells that can potentially restore lost vision caused by loss of photoreceptor cells in RP and AMD.

  1. Allogeneic hematopoietic stem-cell transplantation for adult and adolescent hemophagocytic lymphohistiocytosis: a single center analysis.

    PubMed

    Fu, Li; Wang, Jingshi; Wei, Na; Wu, Lin; Wang, Yini; Huang, Wenqiu; Zhang, Jia; Liu, Jinli; Wang, Zhao

    2016-11-01

    Myeloablative conditioning-based allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of adult and adolescent hemophagocytic lymphohistiocytosis (HLH) is rarely reported. We conducted a retrospective study of 30 adult and adolescent HLH transplanted for primary HLH (n = 4), tumor-HLH (n = 8), EBV-HLH (n = 14), and underlying disease-unknown (UDU)-HLH (n = 4). Peripheral blood stem cells (PBSCs) were the stem-cell source in all patients. Twenty-three patients were transplanted from HLA-haploidentical family donors, six from HLA-identical sibling donors, and one from a matched unrelated donor. Four patients appeared with mixed chimerism (MC), and no patient presented with graft failure. There was a high risk for EBV reactivation with an incidence of 47 %. Two patients developed post-transplant lymphoproliferative disorder (PTLD) and three were considered primary disease recurrent. With a median follow-up of 26 months, 19 patients survived and 11 patients died. The estimated 2-year overall survival (OS) was 63.3 ± 8.8 % in all patients, 100 % in primary HLH, 64.3 ± 12.8 % in EBV-HLH, 50.0 ± 17.7 % in tumor-HLH, and 50.0 ± 25.0 % in UDU-HLH. Myeloablative conditioning-based allo-HSCT is an effective treatment for adult and adolescent HLH to achieve complete remission and long-term survival.

  2. Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents.

    PubMed

    Zhou, June; Keenan, Michael J; Fernandez-Kim, Sun Ok; Pistell, Paul J; Ingram, Donald K; Li, Bing; Raggio, Anne M; Shen, Li; Zhang, Hanjie; McCutcheon, Kathleen L; Tulley, Richard T; Blackman, Marc R; Keller, Jeffrey N; Martin, Roy J

    2013-11-01

    Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (i) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (ii) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (iii) a higher serum active glucagon-like peptide-1 (GLP-1). Then, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (i) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and (ii) GLP-1 is important in the optimal feeding response to a fast.

  3. Brain Stem and Entire Spinal Leptomeningeal Dissemination of Supratentorial Glioblastoma Multiforme in a Patient during Postoperative Radiochemotherapy

    PubMed Central

    Kong, Xiangyi; Wang, Yu; Liu, Shuai; Chen, Keyin; Zhou, Qiangyi; Yan, Chengrui; He, Huayu; Gao, Jun; Guan, Jian; Yang, Yi; Li, Yongning; Xing, Bing; Wang, Renzhi; Ma, Wenbin

    2015-01-01

    Abstract Glioblastoma multiforme (GBM) is the most common primary malignancy of the central nervous system in adults. Macroscopically evident and symptomatic spinal metastases occur rarely. Autopsy series suggest that approximately 25% of patients with intracranial GBM have evidence of spinal subarachnoid seeding, although the exact incidence is not known as postmortem examination of the spine is not routinely performed.1–3 Herein, we present a rare case of symptomatic brain stem and entire spinal dissemination of GBM in a 36-year-old patient during postoperative adjuvant radiochemotherapy with temozolomide and cisplatin. Visual deterioration, intractable stomachache, and limb paralysis were the main clinical features. The results of cytological and immunohistochemical tests on the cerebrospinal fluid cells were highly suggestive of spinal leptomeningeal dissemination. After 1 month, the patient's overall condition deteriorated and succumbed to his disease. To the best of our knowledge, this is the first reported case of GBM dissemination presenting in this manner. Because GBM extracranial dissemination is rare, we also reviewed pertinent literature regarding this uncommon entity. Although metastases to spinal cord from GBM are uncommon, it is always important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern. PMID:26091464

  4. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells.

    PubMed

    Barker, Nick; Clevers, Hans

    2010-05-01

    Molecular markers are used to characterize and track adult stem cells. Colon cancer research has led to the identification of 2 related receptors, leucine-rich repeat-containing, G-protein-coupled receptors (Lgr)5 and Lgr6, that are expressed by small populations of cells in a variety of adult organs. Genetic mouse models have allowed the visualization, isolation, and genetic marking of Lgr5(+ve) and Lgr6(+ve) cells and provided evidence that they are stem cells. The Lgr5(+ve) cells were found to occupy locations not commonly associated with stem cells in the stomach, small intestine, colon, and hair follicles. A multipotent population of skin stem cells express Lgr6. Single Lgr5(+ve) stem cells from the small intestine and the stomach can be cultured into long-lived organoids. Further studies of these markers might reveal adult stem cell populations in additional tissues. Identification of the ligands for Lgr5 and 6 will help elucidate stem cell functions and modes of intracellular signaling.

  5. Preparation of adult muscle fiber-associated stem/precursor cells.

    PubMed

    Conboy, Michael J; Conboy, Irina M

    2010-01-01

    In our studies of muscle regeneration we have developed, modified, and optimized techniques to isolate and study the stem and precursor cells to muscle tissue. Our goals have been to obtain for study muscle fibers in bulk, or the fiber-associated cells, separately from the other cells found in muscle. Using these techniques, myofiber-associated cells may be isolated from neonatal through adult muscle, from resting or from regenerating muscle, thus allowing one to investigate the cellular populations participating during the time course of these events. The protocol is applicable to any age and condition of muscle and may be adapted for other tissues.

  6. Morphological and parametric estimation of fetal neural stem cell migratory capacity in the rat brain.

    PubMed

    Flexman, J A; Cross, D J; Kim, Y; Minoshima, S

    2007-01-01

    Magnetic resonance imaging (MRI) can non-invasively monitor the migratory behavior of magnetically labeled stem cells after transplantation. Signal changes associated with the clearance of the contrast agent due to cell death and leaked tracer in the interstitial space must be better understood in order to accurately interpret imaging results. In this study, fetal neural stem cells were labeled with superparamagnetic iron oxide (SPIO) particles and transplanted into the corpus callosum of the adult rat. MRI was performed on the day of transplantation and at one week. Control subjects received injections of either non-viable, labeled cells or loose SPIO particles. Two quantitative image analysis algorithms were developed to evaluate imaging results: 1) signal intensity drop-out areas were segmented and compared on a pixel-wise basis between initial and one week images; and 2) signal intensity profiles of transplanted materials at one week were parametrically modeled to estimate migration speed. Segmentation results showed that the number of pixels segmented at one week was significantly greater than the initial number of segmented pixels for subjects receiving injections of viable cells as compared to controls (p<0.05). The average speed of migration of viable cells along the corpus callosum was 69.2+/-41.1 microm/d and was significantly higher than controls (p<0.05). This study demonstrates an in vivo assay to quantitatively evaluate stem cell migration that can be used in different experimental paradigms.

  7. MicroRNA network changes in the brain stem underlie the development of hypertension.

    PubMed

    DeCicco, Danielle; Zhu, Haisun; Brureau, Anthony; Schwaber, James S; Vadigepalli, Rajanikanth

    2015-09-01

    Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension.

  8. Delineating multiple functions of VEGF-A in the adult brain.

    PubMed

    Licht, Tamar; Keshet, Eli

    2013-05-01

    Vascular endothelial growth factor-A (abbreviated throughout this review as VEGF) is mostly known for its angiogenic activity, for its activity as a vascular permeability factor, and for its vascular survival activity [1]. There is a growing body of evidence, however, that VEGF fulfills additional less 'traditional' functions in multiple organs, both during development, as well as homeostatic functions in fully developed organs. This review focuses on the multiple roles of VEGF in the adult brain and is less concerned with the roles played by VEGF during brain development, functions described elsewhere in this review series. Most functions of VEGF that are essential for proper brain development are, in fact, dispensable in the adult brain as was clearly demonstrated using a conditional brain-specific VEGF loss-of-function (LOF) approach. Thus, in contrast to VEGF LOF in the developing brain, a process which is detrimental for the growth and survival of blood vessels and leads to massive neuronal apoptosis [2-4], continued signaling by VEGF in the mature brain is no longer required for maintaining already established cerebral vasculature and its inhibition does not cause appreciable vessel regression, hypoxia or apoptosis [4-7]. Yet, VEGF continues to be expressed in the adult brain in a constitutive manner. Moreover, VEGF is expressed in the adult brain in a region-specific manner and in distinctive spatial patterns incompatible with an angiogenic role (see below), strongly suggesting angiogenesis-independent and possibly also perfusion-independent functions. Here we review current knowledge on some of these 'non-traditional', often unexpected homeostatic VEGF functions, including those unrelated to its effects on the brain vasculature. These effects could be mediated directly (on non-vascular cells expressing cognate VEGF receptors) or indirectly (via the endothelium). Experimental approaches aimed at distinguishing between these possibilities for each particular

  9. Receptor protein tyrosine phosphatase σ binds to neurons in the adult mouse brain

    PubMed Central

    Yi, Jae-Hyuk; Katagiri, Yasuhiro; Yu, Panpan; Lourie, Jacob; Bangayan, Nathanael J.; Symes, Aviva J.; Geller, Herbert M.

    2014-01-01

    The role of type IIA receptor protein tyrosine phosphatases (RPTPs), which includes LAR, RPTPσ and RPTPδ, in the nervous system is becoming increasingly recognized. Evidence supports a significant role for these RPTPs during the development of the nervous system as well as after injury, and mutations in RPTPs are associated with human disease. However, a major open question is the nature of the ligands that interact with type IIA RPTPs in the adult brain. Candidates include several different proteins as well as the glycosaminoglycan chains of proteoglycans. In order to investigate this problem, we used a receptor affinity probe assay with RPTPσ-AP fusion proteins on sections of adult mouse brain and to cultured neurons. Our results demonstrate that the major binding sites for RPTPσ in adult mouse brain are on neurons and are not proteoglycan GAG chains, as RPTPσ binding overlaps with the neuronal marker NeuN and was not significantly altered by treatments which eliminate chondroitin sulfate, heparan sulfate, or both. We also demonstrate no overlap of binding of RPTPσ with perineuronal nets, and a unique modulation of RPTPσ binding to brain by divalent cations. Our data therefore point to neuronal proteins, rather than CSPGs, as being the ligands for RPTPσ in the adult, uninjured brain. PMID:24530640

  10. Using network science to evaluate exercise-associated brain changes in older adults.

    PubMed

    Burdette, Jonathan H; Laurienti, Paul J; Espeland, Mark A; Morgan, Ashley; Telesford, Qawi; Vechlekar, Crystal D; Hayasaka, Satoru; Jennings, Janine M; Katula, Jeffrey A; Kraft, Robert A; Rejeski, W Jack

    2010-01-01

    Literature has shown that exercise is beneficial for cognitive function in older adults and that aerobic fitness is associated with increased hippocampal tissue and blood volumes. The current study used novel network science methods to shed light on the neurophysiological implications of exercise-induced changes in the hippocampus of older adults. Participants represented a volunteer subgroup of older adults that were part of either the exercise training (ET) or healthy aging educational control (HAC) treatment arms from the Seniors Health and Activity Research Program Pilot (SHARP-P) trial. Following the 4-month interventions, MRI measures of resting brain blood flow and connectivity were performed. The ET group's hippocampal cerebral blood flow (CBF) exhibited statistically significant increases compared to the HAC group. Novel whole-brain network connectivity analyses showed greater connectivity in the hippocampi of the ET participants compared to HAC. Furthermore, the hippocampus was consistently shown to be within the same network neighborhood (module) as the anterior cingulate cortex only within the ET group. Thus, within the ET group, the hippocampus and anterior cingulate were highly interconnected and localized to the same network neighborhood. This project shows the power of network science to investigate potential mechanisms for exercise-induced benefits to the brain in older adults. We show a link between neurological network features and CBF, and it is possible that this alteration of functional brain networks may lead to the known improvement in cognitive function among older adults following exercise.

  11. Neuronal degeneration in the brain of the brindled mouse. Histochemical demonstration of decreased cytochrome oxidase activity in the cerebellum and brain stem.

    PubMed

    Yoshimura, N

    1988-06-01

    In order to investigate the levels of cytochrome oxidase activity in neuronal mitochondria in the brain of the brindled mouse hemizygote (BM), the cerebella and brain stems from 12 pairs of brindled and normal littermates aged 13-16 days were examined. The diaminobenzidine method for light- and electronmicroscopic histochemistry was adopted. Light microscopy revealed that mitochondria in the normal cerebellum showed an intensely positive reaction to diaminobenzidine, whereas those in the BM cerebellum showed a very weak reaction indicating an evident reduction of cytochrome oxidase activity. Electron microscopy disclosed a diaminobenzidine-OsO4 product densely appearing on the inner membranes of most mitochondria in Purkinje cells in the normal cerebellum. However, it was very faint or absent in those in the BM cerebellum. The same was true in Golgi II cells, granule cells, glomeruli and brain stem nuclei, but the degree of reduction was not uniform among these structures. In conclusion, there is not only a generalized reduction of cytochrome oxidase activity but also a topographical predilection of areas showing a reduction of the enzyme in the BM cerebellum and brain stem. These facts may explain the pathogenesis of neuronal degeneration in the brain of the BM.

  12. Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration.

    PubMed

    Wagner, Daniel E; Wang, Irving E; Reddien, Peter W

    2011-05-13

    Pluripotent cells in the embryo can generate all cell types, but lineage-restricted cells are generally thought to replenish adult tissues. Planarians are flatworms and regenerate from tiny body fragments, a process requiring a population of proliferating cells (neoblasts). Whether regeneration is accomplished by pluripotent cells or by the collective activity of multiple lineage-restricted cell types is unknown. We used ionizing radiation and single-cell transplantation to identify neoblasts that can form large descendant-cell colonies in vivo. These clonogenic neoblasts (cNeoblasts) produce cells that differentiate into neuronal, intestinal, and other known postmitotic cell types and are distributed throughout the body. Single transplanted cNeoblasts restored regeneration in lethally irradiated hosts. We conclude that broadly distributed, adult pluripotent stem cells underlie the remarkable regenerative abilities of planarians.

  13. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus.

    PubMed

    Li, Guangnan; Fang, Li; Fernández, Gloria; Pleasure, Samuel J

    2013-05-22

    Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus.

  14. Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults

    PubMed Central

    Gallen, Courtney L.; Baniqued, Pauline L.; Chapman, Sandra B.; Aslan, Sina; Keebler, Molly; Didehbani, Nyaz; D’Esposito, Mark

    2016-01-01

    Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating “associative” functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration: ClinicalTrials.gov, NCT#00977418 PMID:28006029

  15. Using brain slice cultures of mouse brain to assess the effect of growth factors on differentiation of bone marrow derived stem cells.

    PubMed

    Bratincsák, András; Lonyai, Anna; Shahar, Tal; Hansen, Arne; Tóth, Zsuzsanna E; Mezey, Eva

    2007-03-30

    Bone marrow derived stem cells (BMDSCs) have been reported to form neurons and supportive cells in the brain. We describe a technique that combines the simplicity of in vitro studies with many of the advantages of in vivo experiments. We cultured mouse brain slices, deposited GFP-tagged BMDSCs evenly distributed on their surfaces, and then added test factors to the culture medium. Addition of both SDF-1 and EGF resulted in morphological changes of BMDSC and in the induction of islet-1, a marker of neuroepithelial progenitors. We conclude that organotypic tissue culture (OTC) may allow us to detect the effects of exogenous factors on the differentiation of BMDSCs (or any other type of stem cells) in an environment that may resemble the CNS after brain injury. Once such factors have been identified they could be evaluated for tissue regeneration in more complex, whole animal models.

  16. Brain function differences in language processing in children and adults with autism.

    PubMed

    Williams, Diane L; Cherkassky, Vladimir L; Mason, Robert A; Keller, Timothy A; Minshew, Nancy J; Just, Marcel Adam

    2013-08-01

    Comparison of brain function between children and adults with autism provides an understanding of the effects of the disorder and associated maturational differences on language processing. Functional imaging (functional magnetic resonance imaging) was used to examine brain activation and cortical synchronization during the processing of literal and ironic texts in 15 children with autism, 14 children with typical development, 13 adults with autism, and 12 adult controls. Both the children and adults with autism had lower functional connectivity (synchronization of brain activity among activated areas) than their age and ability comparison group in the left hemisphere language network during irony processing, and neither autism group had an increase in functional connectivity in response to increased task demands. Activation differences for the literal and irony conditions occurred in key language-processing regions (left middle temporal, left pars triangularis, left pars opercularis, left medial frontal, and right middle temporal). The children and adults with autism differed from each other in the use of some brain regions during the irony task, with the adults with autism having activation levels similar to those of the control groups. Overall, the children and adults with autism differed from the adult and child controls in (a) the degree of network coordination, (b) the distribution of the workload among member nodes, and (3) the dynamic recruitment of regions in response to text content. Moreover, the differences between the two autism age groups may be indicative of positive changes in the neural function related to language processing associated with maturation and/or educational experience.

  17. Endogenous Neural Stem/Progenitor Cells Stabilize the Cortical Microenvironment after Traumatic Brain Injury

    PubMed Central

    Dixon, Kirsty J.; Theus, Michelle H.; Nelersa, Claudiu M.; Mier, Jose; Travieso, Lissette G.; Yu, Tzong-Shiue; Kernie, Steven G.

    2015-01-01

    Abstract Although a myriad of pathological responses contribute to traumatic brain injury (TBI), cerebral dysfunction has been closely linked to cell death mechanisms. A number of therapeutic strategies have been studied in an attempt to minimize or ameliorate tissue damage; however, few studies have evaluated the inherent protective capacity of the brain. Endogenous neural stem/progenitor cells (NSPCs) reside in distinct brain regions and have been shown to respond to tissue damage by migrating to regions of injury. Until now, it remained unknown whether these cells have the capacity to promote endogenous repair. We ablated NSPCs in the subventricular zone to examine their contribution to the injury microenvironment after controlled cortical impact (CCI) injury. Studies were performed in transgenic mice expressing the herpes simplex virus thymidine kinase gene under the control of the nestinδ promoter exposed to CCI injury. Two weeks after CCI injury, mice deficient in NSPCs had reduced neuronal survival in the perilesional cortex and fewer Iba-1-positive and glial fibrillary acidic protein-positive glial cells but increased glial hypertrophy at the injury site. These findings suggest that the presence of NSPCs play a supportive role in the cortex to promote neuronal survival and glial cell expansion after TBI injury, which corresponds with improvements in motor function. We conclude that enhancing this endogenous response may have acute protective roles after TBI. PMID:25290253

  18. ABAEnrichment: an R package to test for gene set expression enrichment in the adult and developing human brain.

    PubMed

    Grote, Steffi; Prüfer, Kay; Kelso, Janet; Dannemann, Michael

    2016-10-15

    We present ABAEnrichment, an R package that tests for expression enrichment in specific brain regions at different developmental stages using expression information gathered from multiple regions of the adult and developing human brain, together with ontologically organized structural information about the brain, both provided by the Allen Brain Atlas. We validate ABAEnrichment by successfully recovering the origin of gene sets identified in specific brain cell-types and developmental stages.

  19. The effects of sleep deprivation on brain functioning in older adults.

    PubMed

    Almklov, Erin L; Drummond, Sean P A; Orff, Henry; Alhassoon, Omar M

    2015-01-01

    Few studies have examined the effects of total sleep deprivation (TSD) on cognitive performance and brain activation using functional MRI (fMRI) in older adults. The current study examines blood oxygen level-dependent (BOLD) activation in older adults and younger adults during the sustained attention (GO) and response inhibition (NOGO) portions of a GO-NOGO cognitive task following 36 hr of total sleep deprivation. No significant performance differences were observed between the groups on the behavioral outcome measures of total hits and false alarms. Neuroimaging results, however, revealed a significant interaction between age-group and sleep-deprivation status. Specifically, older adults showed greater BOLD activation as compared to younger adults after 36 hours total sleep deprivation in brain regions typically associated with attention and inhibitory processes. These results suggest in order for older adults to perform the GO-NOGO task effectively after sleep deprivation, they rely on compensatory recruitment of brain regions that aide in the maintenance of cognitive performance.

  20. Educating the adult brain: How the neuroscience of learning can inform educational policy

    NASA Astrophysics Data System (ADS)

    Knowland, Victoria C. P.; Thomas, Michael S. C.

    2014-05-01

    The acquisition of new skills in adulthood can positively affect an individual's quality of life, including their earning potential. In some cases, such as the learning of literacy in developing countries, it can provide an avenue to escape from poverty. In developed countries, job retraining in adulthood contributes to the flexibility of labour markets. For all adults, learning opportunities increase participation in society and family life. However, the popular view is that adults are less able to learn for an intrinsic reason: their brains are less plastic than in childhood. This article reviews what is currently known from neuroscientific research about how brain plasticity changes with age, with a particular focus on the ability to acquire new skills in adulthood. Anchoring their review in the examples of the adult acquisition of literacy and new motor skills, the authors address five specific questions: (1) Are sensitive periods in brain development relevant to learning complex educational skills like literacy? (2) Can adults become proficient in a new skill? (3) Can everyone learn equally effectively in adulthood? (4) What is the role of the learning environment? (5) Does adult education cost too much? They identify areas where further research is needed and conclude with a summary of principles for enhancing adult learning now established on a neuroscience foundation.

  1. The effects of acetaldehyde on nicotine-induced transmitter levels in young and adult brain areas.

    PubMed

    Sershen, H; Shearman, E; Fallon, S; Chakraborty, G; Smiley, J; Lajtha, A

    2009-08-14

    The aim of the present study was to examine the effect of acetaldehyde administration on neurotransmitters in the presence of nicotine in brain areas associated with cognition and reward. We assayed these effects via microdialysis in conscious freely moving male Sprague-Dawley rats. It was reported that low doses of acetaldehyde enhance nicotine self-administration in young, but not in adult rats. Since nicotine enhances reward and learning, while acetaldehyde is reported to enhance reward but inhibit learning, acetaldehyde thus would be likely to stimulate reward without stimulating learning. We hoped that examining the effects of acetaldehyde (on nicotine-mediated neurotransmitter changes) would help to distinguish reward mechanisms less influenced by learning mechanisms. To avoid the aversive effect of acetaldehyde, we used a low dose of acetaldehyde (0.16 mg/kg) administered after nicotine (0.3mg/kg). We analyzed six brain regions: nucleus accumbens shell (NAccS), ventral tegmental area (VTA), ventral and dorsal hippocampus (VH and DH), and prefrontal and medial temporal cortex (PFC, MTC), assaying dopamine (DA), norepinephrine (NE) and serotonin (5-HT) and their metabolites in young and adult rats. The effect of acetaldehyde on nicotine-induced transmitter changes was different in young as compared to adult rat brain regions. In the NAccS of the young, DA was not affected while NE and 5-HT were increased. In the adult in this area DA and NE were decreased, while 5-HT was not altered. In other areas also in many cases, the effect of acetaldehyde in the young and in the adult was different. As an example, acetaldehyde administration increased NE in young and decreased NE in adult DH. We found stimulation of nicotine-induced changes by acetaldehyde in seven instances - six of these were observed in areas in young brain, NE in four areas (NAccS, DH, VH, and PFC), and 5-HT in two (NAccS and DH). Only one increase was noted in adult brain (DA in VTA). Inhibition of

  2. Fetal Alcohol Exposure Reduces Adult Brain Plasticity. Science Briefs

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2007

    2007-01-01

    "Science Briefs" summarize the findings and implications of a recent study in basic science or clinical research. This Brief summarizes the findings and implications of "Moderate Fetal Alcohol Exposure Impairs the Neurogenic Response to an Enriched Environment in Adult Mice" (I. Y. Choi; A. M. Allan; and L. A. Cunningham). Observations of mice…

  3. The Influence of Modified Silica Nanomaterials on Adult<