Neural stem cells hold the key to innovative new treatments for age-associated degeneration and traumatic injury to the brain and spinal cord. We hypothesized that the in vivo induced pluripotent stem cells or neural stem cells through \\
Ti-Fei Yuan; Oscar Arias-Carrión
Stem cells have a potential of gene therapy for regenerative medicine. Among various stem cells, spermatogonial stem cells have a unique characteristic in which neighboring cells can be connected by intercellular bridges. However, the roles of intercellular bridges for stem cell self-renewal, differentiation, and proliferation remain to be elucidated. Here, we show not only the characteristics of testis-expressed gene 14
Naoki Iwamori; Tokuko Iwamori; Martin M. Matzuk
Most dentate vertebrates, including humans, replace their teeth and yet the process is poorly understood. Here, we investigate whether dental epithelial stem cells exist in a polyphyodont species, the leopard gecko (Eublepharis macularius). Since the gecko dental epithelium lacks a histologically distinct site for stem cells analogous to the mammalian hair follicle bulge, we performed a pulse-chase experiment on juvenile geckos to identify label-retaining cells (LRCs). We detected LRCs exclusively on the lingual side of the dental lamina, which exhibits low proliferation rates and is not involved in tooth morphogenesis. Lingual LRCs were organized into pockets of high density close to the successional lamina. A subset of the LRCs expresses Lgr5 and other genes that are markers of adult stem cells in mammals. Also similar to mammalian stem cells, the LRCs appear to proliferate in response to gain of function of the canonical Wnt pathway. We suggest that the LRCs in the lingual dental lamina represent a population of stem cells, the immediate descendents of which form the successional lamina and, ultimately, the replacement teeth in the gecko. Furthermore, their location on the non-tooth-forming side of the dental lamina implies that dental stem cells are sequestered from signals that might otherwise induce them to differentiate. PMID:20876646
Handrigan, Gregory R; Leung, Kelvin J; Richman, Joy M
Adult stem cell research has drawn a lot of attention by many researchers, due to its medical hope of cell replacement or regenerative therapy for diabetes patients. Despite the many research efforts to date, there is no consensus on the existence of stem cells in adult pancreas. Genetic lineage tracing experiments have put into serious doubt whether ?-cell neogenesis from stem/progenitor cells takes place postnatally. Different in vitro experiments have suggested centroacinar, ductal, acinar, stellate, or yet unidentified clonigenic cells as candidate ?-cell progenitors. As in the rest of the adult stem cell field, sound and promising observations have been made. However, these observations still need to be replicated. As an alternative to committed stem/progenitor cells in the pancreas, transdifferentiation or lineage reprogramming of exocrine acinar and endocrine ?-cells may be used to generate new ?-cells. At present, it is unclear which approach is most medically promising. This article highlights the progress being made in knowledge about tissue stem cells, their existence and availability for therapy in diabetes. Particular attention is given to the assessment of methods to verify the existence of tissue stem cells.
Houbracken, Isabelle; Bouwens, Luc
The appeal of using embryonic stem (ES) cells for regenerative medicine lies in their pluripotency and resulting ability to differentiate into all somatic cell types. While graft rejection remains the greatest hurdle to their use in the clinic, several approaches have been proposed to protect the allogeneic ES cell-derived grafts from host immunity: the creation of nuclear transfer human ES
Kathy O. Lui; Herman Waldmann; Paul J. Fairchild
Phenotypic evolutionary models have been used with great success in many areas of biology, but thus far have not been applied to the study of stem cells except for investigations of cancer. We develop a framework that allows such modeling techniques to be applied to stem cells more generally. The fundamental modeling structure is the stochastic kinetics of stem cells
Marc Mangel; Michael B. Bonsall; Mark Rees
Abstract Phenotypic evolutionary models have been used with great success in many areas of biology, but thus far have not been applied to the study of stem cells except for investigations of cancer. We develop,a framework,that allows such modeling techniques,to be applied to stem,cells more,generally. The fundamental,modeling,structure is the stochastic kinetics of stem cells in their niche and of transit
Marc Mangel; Michael B. Bonsall
Tissue stem cells have self-renewal capability throughout their whole life, which is high enough to lead to the accumulation of DNA damage in a stem cell pool. Whether radiation-induced damage accumulates in tissue stem cells remains unknown, but could be investigated if the fate of tissue stem cells could be followed after irradiation. To realize this goal, we used an Lgr5-dependent lineage tracing system that allows the conditional in vivo labeling of Lgr5(+) intestinal stem cells and their progeny. We found that radiation induced loss of Lgr5(+) stem cells in the colon, but not in the duodenum. Interestingly, the loss of colonic Lgr5(+) cells was compensated by de novo production of Lgr5(+) cells, which increased after irradiation. These findings show that ionizing radiation effectively stimulates the turnover of colonic Lgr5(+) stem cells, implying that radiation-induced damage does not accumulate in the colonic Lgr5(+) stem cells by this mechanism. PMID:23627781
Otsuka, Kensuke; Hamada, Nobuyuki; Magae, Junji; Matsumoto, Hideki; Hoshi, Yuko; Iwasaki, Toshiyasu
Human adult dental pulp stem cells (DPSCs), derived from third molar teeth, are multipotent and have the capacity to differentiate into neurons under inductive conditions both in vitro and following transplantation into the avian embryo. In this study, we demonstrate that the intracerebral transplantation of human DPSCs 24 hours following focal cerebral ischemia in a rodent model resulted in significant improvement in forelimb sensorimotor function at 4 weeks post-treatment. At this time, 2.3 ± 0.7% of engrafted cells had survived in the poststroke brain and demonstrated targeted migration toward the stroke lesion. In the peri-infarct striatum, transplanted DPSCs differentiated into astrocytes in preference to neurons. Our data suggest that the dominant mechanism of action underlying DPSC treatment that resulted in enhanced functional recovery is unlikely to be due to neural replacement. Functional improvement is more likely to be mediated through DPSC-dependent paracrine effects. This study provides preclinical evidence for the future use of human DPSCs in cell therapy to improve outcome in stroke patients.
Leong, Wai Khay; Henshall, Tanya L.; Arthur, Agnes; Kremer, Karlea L.; Lewis, Martin D.; Helps, Stephen C.; Field, John; Hamilton-Bruce, Monica A.; Warming, Scott; Manavis, Jim; Vink, Robert; Gronthos, Stan
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
Neirinckx, Virginie; Marquet, Alice; Coste, Cécile; Rogister, Bernard; Wislet-Gendebien, Sabine
Hematopoietic stem cell transplantation (HSCT) is a treatment option for both malignant and nonmalignant disorders. HSCT patients remain at high risk for multiorgan failure, with previous studies noting mortality rates exceeding 90% when mechanical ventilation (MV) is required. We propose that advancements in critical care management and HSCT practices have improved these dismal outcomes. We performed a retrospective review of admissions to our bone marrow transplant unit between 2006 and 2010. All HSCT recipients requiring admission to the bone marrow transplant unit who received MV or renal replacement therapy (RRT) were evaluated. A total of 68 patients required MV. Twenty patients required RRT, all of whom required MV. Fifty-nine of the 68 ventilated patients died, for an overall mortality rate of 86.8%. The presence of renal failure and concomitant respiratory or liver dysfunction at the time of intubation was associated with a mortality rate of 100%. High mortality persists in our HSCT population requiring artificial support despite overall advances in critical care and HSCT practices. Critical care triage and management decisions in this high-risk population remain challenging. PMID:23025989
Gilbert, Christopher; Vasu, Tajender S; Baram, Michael
Background Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1G93A rats leads to a moderate therapeutical effect as evidenced by local ?-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1G93A animals. Methods/Principal Findings Presymptomatic SOD1G93A rats (60–65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1G93A rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1G93A rats protected ?-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to ?-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50–65%) loss of large caliber descending motor axons. Conclusions/Significance These data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.
Hefferan, Michael P.; Galik, Jan; Kakinohana, Osamu; Sekerkova, Gabriela; Santucci, Camila; Marsala, Silvia; Navarro, Roman; Hruska-Plochan, Marian; Johe, Karl; Feldman, Eva; Cleveland, Don W.; Marsala, Martin
Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon. These self-renewing clones give rise to all fundamental neural lineages in vitro. Following transplantation into germinal zones of the newborn mouse brain they participate in aspects of normal development, including migration along established migratory pathways to disseminated central nervous system regions, differentiation into multiple developmentally
Jonathan D. Flax; Sanjay Aurora; Chunhua Yang; Clemence Simonin; Ann Marie Wills; Lori L. Billinghurst; Moncef Jendoubi; Richard L. Sidman; John H. Wolfe; Seung U. Kim; Evan Y. Snyder
Pediatric stem cell transplant (SCT) recipients commonly develop acute renal failure (ARF). We report the demographic and\\u000a survival data of pediatric SCT patients enrolled in the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT)\\u000a Registry. Since 1 January 2001, 51\\/370 (13.8%) patients entered in the ppCRRT Registry had received a SCT. Median age was\\u000a 13.63 (0.53–23.52) years. The primary reasons for
Francisco X. Flores; Patrick D. Brophy; Jordan M. Symons; James D. Fortenberry; Annabelle N. Chua; Steven R. Alexander; John D. Mahan; Timothy E. Bunchman; Douglas Blowey; Michael J. G. Somers; Michelle Baum; Richard Hackbarth; Deepa Chand; Kevin McBryde; Mark Benfield; Stuart L. Goldstein
The Ercc1-Xpf heterodimer, a highly conserved structure-specific endonuclease, functions in multiple DNA repair pathways that are pivotal for maintaining genome stability, including nucleotide excision repair, interstrand crosslink repair and homologous recombination. Ercc1-Xpf incises double-stranded DNA at double-strand/single-strand junctions, making it an ideal enzyme for processing DNA structures that contain partially unwound strands. Here we demonstrate that although Ercc1 is dispensable for recombination between sister chromatids, it is essential for targeted gene replacement in mouse embryonic stem cells. Surprisingly, the role of Ercc1-Xpf in gene targeting is distinct from its previously identified role in removing nonhomologous termini from recombination intermediates because it was required irrespective of whether the ends of the DNA targeting constructs were heterologous or homologous to the genomic locus. Our observations have implications for the mechanism of gene targeting in mammalian cells and define a new role for Ercc1-Xpf in mammalian homologous recombination. We propose a model for the mechanism of targeted gene replacement that invokes a role for Ercc1-Xpf in making the recipient genomic locus receptive for gene replacement. PMID:11707424
Niedernhofer, L J; Essers, J; Weeda, G; Beverloo, B; de Wit, J; Muijtjens, M; Odijk, H; Hoeijmakers, J H; Kanaar, R
Allogeneic hematopoietic stem cell transplantation (HSCT) use has expanded markedly to treat different disorders like hematologic malignancies, immunodeficiency, and inborn errors of metabolism. However, it is commonly associated with complications that limit the benefit of this therapy. Acute renal failure occurs commonly after HSCT and results in increased risk of mortality. In many instances, children post-HSCT develop acute renal insufficiency in the context of other organ failure, necessitating intensive care unit admission for management. Recently, continuous renal replacement therapy (CRRT) has emerged as the favored modality of renal replacement therapy in the care of critically ill children who are hemodynamically unstable. Currently, CRRT is being utilized more often in the care of critically ill post- HSCT children to treat renal failure or to prevent fluid overload (FO). FO > 20% has been shown in many studies to be an independent risk of mortality in critically ill children and therefore, many clinicians will initiate this therapy due to FO even without overt renal failure. CRRT may be beneficial in disease processes as acute lung injury due to removal of fluid. CRRT results in improved oxygenation in post-HSCT children with acute lung injury and this improvement is sustained for at least 48 hours after initiation of this therapy. Survival in post-HSCT children requiring this therapy ranges from 17% to 45%, however, long term survival is still poor. This review will discuss current practice of CRRT in children post-HSCT, as well as future directions. PMID:22834995
Elbahlawan, Lama; Morrison, R Ray
In the adult, tissue-specific stem cells are thought to be responsible for the replacement of differentiated cells within continuously regenerating tissues, such as the liver, skin, and blood system. In this review, we will consider the factors that influence stem cell fate, taking as a primary example the cell fate determination of hematopoietic stem cells.
A J Wagers; J L Christensen; I L Weissman
Advanced therapies combating acute and chronic skin wounds are likely to be brought about using our knowledge of regenerative medicine coupled with appropriately tissue-engineered skin substitutes. At the present time, there are no models of an artificial skin that completely replicate normal uninjured skin. Natural biopolymers such as collagen and fibronectin have been investigated as potential sources of biomaterial to which cells can attach. The first generation of degradable polymers used in tissue engineering were adapted from other surgical uses and have drawbacks in terms of mechanical and degradation properties. This has led to the development of synthetic degradable gels primarily as a way to deliver cells and/or molecules in situ, the so-called smart matrix technology. Tissue or organ repair is usually accompanied by fibrotic reactions that result in the production of a scar. Certain mammalian tissues, however, have a capacity for complete regeneration without scarring; good examples include embryonic or foetal skin and the ear of the MRL/MpJ mouse. Investigations of these model systems reveal that in order to achieve such complete regeneration, the inflammatory response is altered such that the extent of fibrosis and scarring is diminished. From studies on the limited examples of mammalian regeneration, it may also be possible to exploit such models to further clarify the regenerative process. The challenge is to identify the factors and cytokines expressed during regeneration and incorporate them to create a smart matrix for use in a skin equivalent. Recent advances in the use of DNA microarray and proteomic technology are likely to aid the identification of such molecules. This, coupled with recent advances in non-viral gene delivery and stem cell technologies, may also contribute to novel approaches that would generate a skin replacement whose materials technology was based not only upon intelligent design, but also upon the molecules involved in the process of regeneration. PMID:17251138
Metcalfe, Anthony D; Ferguson, Mark W J
Stem cells always balance between self-renewal and differentiation. Hence, stem cell culture parameters are critical and need to be continuously refined according to progress in our stem cell biology understanding and the latest technological developments. This led to the progressive replacement of ill-defined additives such as serum or feeder cell layers by recombinant cytokines or growth factors. Another example is the control of the oxygen pressure. For many years cell cultures have been done under atmospheric oxygen pressure which is much higher than the one experienced by stem cells in vivo. A consequence of cell metabolism is that cell culture conditions are constantly changing. Therefore, the development of high sensitive monitoring processes and control algorithms is required for ensuring cell culture medium homeostasis. Stem cells also sense the physical constraints of their microenvironment. Rigidity, stiffness and geometry of the culture substrate influence stem cell fate. Hence, nanotopography is probably as important as medium formulation in the optimization of stem cell culture conditions. Recent advances include the development of synthetic bioinformative substrates designed at the micro- and nanoscale level. On going research in many different fields including stem cell biology, nanotechnology, and bioengineering suggest that our current way to culture cells in Petri dish or flasks will soon be outdated as flying across the Atlantic Ocean in the Lindbergh’s plane.
Van Der Sanden, Boudewijn; Dhobb, Mehdi; Berger, Francois; Wion, Didier
Strategies for cell replacement therapy have been guided by the success in the hematopoietic stem cell field. In this review,\\u000a we discuss the basis of this success and examine whether this stem cell transplant model can be replicated in other systems\\u000a where stem cell therapy is being evaluated. We conclude that identifying the most primitive stem cell and using it
Jingli Cai; Mahendra S. Rao
The lack of adenosine deaminase (ADA) leads to the accumulation of toxic metabolites, resulting in SCID. If the disease is left untreated, it is likely to have a fatal outcome in early infancy. Because hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy with pegylated bovine ADA (PEG-ADA) are both provided in our hospital, we undertook a retrospective longitudinal comparative study of the extent of lymphocyte recovery in two groups of treated ADA-SCID children. Together with classical immunological parameters, we quantified the output of the new B and T cells from the production sites using the ?-deleting recombination excision circle and TCR excision circle assay, and we monitored T cell repertoire diversification. We found that immune reconstitution was different following the two treatments. The stable production of ?-deleting recombination excision circle(+) lymphocytes sustained an increase in B cell number in HSCT-treated patients, whereas in PEG-ADA-treated patients, it was accompanied by a significant and progressive decrease in circulating CD19(+) lymphocytes, which never reached the levels observed in age-matched children. The mobilization of TCR excision circle(+) cells, though lower than in controls, was stable with time after HSCT treatment, leading to a constant peripheral T cell number and to the diversification of the T cell repertoire; however, it was compromised in children receiving prolonged PEG-ADA therapy, whose T cells showed progressively narrowing T cell repertoires. PMID:21057082
Serana, Federico; Sottini, Alessandra; Chiarini, Marco; Zanotti, Cinzia; Ghidini, Claudia; Lanfranchi, Arnalda; Notarangelo, Lucia Dora; Caimi, Luigi; Imberti, Luisa
\\u000a The demonstrated capacity and potential of pluripotent stem cells to repair the damaged tissues holds great promise in development\\u000a of novel cell replacement therapeutics for treating various chronic and degenerative diseases. However, previous reports show\\u000a that stem cell therapy, in autologous and allogeneic settings, triggers immune responses to stem cells as shown by lymphocyte\\u000a infiltration and inflammation. Therefore, an important
Xiao-Feng Yang; Hong Wang
Cardiac stem cell therapy to promote engraftment of de novo beating cardiac muscle cells in cardiomyopathies could potentially improve clinical outcomes for many patients with congestive heart failure. Clinical trials carried out over the last decade for cardiac regeneration have revealed inadequacy of current approaches in cell therapy. Chief among them is the choice of stem cells to achieve the desired outcomes. Initial enthusiasm of adult bone marrow stems cells for myocyte regeneration has largely been relegated to paracrine-driven, donor cell-independent, endogenous cardiac repair. However, true functional restoration in heart failure is likely to require considerable myocyte replacement. In order to match stem cell application to various clinical scenarios, we review the necessity to preprime stem cells towards cardiac fate before myocardial transplantation and if these differentiated stem cells could confer added advantage over current choice of undifferentiated stem cells. We explore differentiation ability of various stem cells to cardiac progenitors/cardiomyocytes and compare their applicability in providing targeted recovery in light of current clinical challenges of cell therapy. PMID:22943934
Mehta, Ashish; Shim, Winston
\\u000a To fully understand the biological meaning of the term stem cell (SC) it is useful to clarify the derivation of the root staminal, even though modern research published in English-speaking journals never seem to use the term staminal. While there are\\u000a no doubts that the term SC originated in the context of two major embryological questions, the continuity of the
Manuela Monti; Carlo Alberto Redi
Although stem cell research is a rather new field in modern medicine, media soon popularized it. The reason for this hype lies in the potential of stem cells to drastically increase quality of life through repairing aging and diseased organs. Nevertheless, the essence of stem cell research is to understand how tissues are maintained during adult life. In this article, we summarize the various types of stem cells and their differentiation potential in vivo and in vitro. We review current clinical applications of stem cells and highlight problems encountered when going from animal studies to clinical practice. Furthermore, we describe the current state of induced pluripotent stem cell technology and applications for disease modelling and cell replacement therapy. PMID:21481037
Leeb, C; Jurga, M; McGuckin, C; Forraz, N; Thallinger, C; Moriggl, R; Kenner, L
Terminal heart failure is characterized by a significant loss of cardiac myocytes. Stem cells represent a possibility for replacing these lostmyocytes but the question of which stem cells are most ideally suited for cell transplantation therapies is still being addressed. Here, we consider human embryonic stem cells (HESC), derived from human embryos in this context. We review the methods used
R. Passier; C. Denning; C. Mummery
Stem cells and progenitor cells in renal tissue. Stem cells and progenitor cells are necessary for repair and regeneration of injured renal tissue. Infiltrating or resident stem cells can contribute to the replacement of lost or damaged tissue. However, the regulation of circulating progenitor cells is not well understood. We have analyzed the effects of erythropoietin on circulating progenitor cells
HERMANN HALLER; KIRSTEN DE GROOT; FERDINAND BAHLMANN; MARLIES ELGER; DANILO FLISER
Dramatic advances in the field of stem cell research have raised the possibility of using these cells to treat a variety of diseases. The eye is an excellent target organ for such cell-based therapeutics due to its ready accessibility, the prevalence of vasculo- and neurodegenerative diseases affecting vision, and the availability of animal models to demonstrate proof of concept. In fact, stem cell therapies have already been applied to the treatment of disease affecting the ocular surface, leading to preservation of vision. Diseases in the back of the eye, such as macular degeneration, diabetic retinopathy, and inherited retinal degenerations, present greater challenges, but rapidly emerging stem cell technologies hold the promise of autologous grafts to stabilize vision loss through cellular replacement or paracrine rescue effects.
Marchetti, Valentina; Krohne, Tim U.; Friedlander, David F.; Friedlander, Martin
Tooth loss compromises human oral health. Although several prosthetic methods, such as artificial denture and dental implants, are clinical therapies to tooth loss problems, they are thought to have safety and usage time issues. Recently, tooth tissue engineering has attracted more and more attention. Stem cell based tissue engineering is thought to be a promising way to replace the missing tooth. Mesenchymal stem cells (MSCs) are multipotent stem cells which can differentiate into a variety of cell types. The potential MSCs for tooth regeneration mainly include stem cells from human exfoliated deciduous teeth (SHEDs), adult dental pulp stem cells (DPSCs), stem cells from the apical part of the papilla (SCAPs), stem cells from the dental follicle (DFSCs), periodontal ligament stem cells (PDLSCs) and bone marrow derived mesenchymal stem cells (BMSCs). This review outlines the recent progress in the mesenchymal stem cells used in tooth regeneration. PMID:20690498
Peng, Li; Ye, Ling; Zhou, Xue-dong
\\u000a Mesenchymal stem cells (MSC) are pluripotent cells that differentiate into cells of mesodermal origin and transdifferentiate\\u000a into ectodermal and endodermal cell types. MSC can transdifferentiate with high efficiency to functional neurons, microglia\\u000a and oligodendrocytes. MSC and neurons can respond to environmental cues such as cytokines, which also affect the development\\u000a to neural cells. Since cytokines and other inflammatory mediators are
Cecile King; Shyam Patel; Treena Livingston Arinzeh; Pranela Rameshwar
The potential of stem cells to replace damaged cells and organs is the subject of public discourse and political debate. Stem\\u000a cell biology is in an explosive phase of growth, but has not yet yielded a fundamental understanding of the molecular control\\u000a of stem cell fate. Surprisingly the role of the gaseous environment in the control of stem cell biology
Permanent loss of cardiomyocytes and scar tissue formation after myocardial infarction (MI) results in an irreversible damage to the cardiac function. Cardiac repair (replacement, restoration, and regeneration) is, therefore, essential to restore function of the heart following MI. Existing therapies lower early mortality rates, prevent additional damage to the heart muscle, and reduce the risk of further heart attacks. However, there is need for treatment to improve the infarcted area by replacing the damaged cells after MI. Thus, the cardiac tissue regeneration with the application of stem cells may be an effective therapeutic option. Recently, interest is more inclined toward myocardial regeneration with the application of stem cells. However, the potential benefits and the ability to improve cardiac function with the stem cell-based therapy need to be further addressed. In this review, we focus on the clinical applications of stem cells in the cardiac repair. PMID:21687345
Krishna, K Ananda; Krishna, K Sai; Berrocal, Ruben; Rao, K S; Sambasiva Rao, K R S
Stem cells undergo regulated trafficking from the developmental stages to the adulthood. Stem cell migration is critical to organize developing organs and likely contributes postnatally to tissue regeneration. Here, we review the molecular mechanisms underlying migration of hematopoietic stem cells, neural stem cells, and primordial germ cells, revealing common operative pathways. PMID:21618080
Magnon, Claire; Lucas, Daniel; Frenette, Paul S
Proteins from the Polycomb group (PcG) are epigenetic chromatin modifiers involved in cancer development and also in the maintenance of embryonic and adult stem cells. The therapeutic potential of stem cells and the growing conviction that tumors contain stem cells highlights the importance of understanding the extrinsic and intrinsic circuitry controlling stem cell fate and their connections to cancer.
Merel E. Valk-Lingbeek; Sophia W. M. Bruggeman; Maarten van Lohuizen
Stem cell research is at the heart of regenerative medicine, which holds great promise for the treatment of many devastating disorders. However, in addition to hurdles posed by well-publicized ethical issues, this emerging field presents many biological challenges. What is a stem cell? How are embryonic stem cells different from adult stem cells? What are the physiological bases for therapeutically
This transcript is based on my The Year in Basic Science lecture at ENDO 2008. I reviewed current data surrounding hormone replacement therapy and the relationship between systemic estrogen plus progestin (E+P) treatment and increased breast cancer risk, and I explored the hypothesis that women who develop breast cancer while on E+P had occult, undiagnosed disease before they started therapy. Beginning with recent hormone replacement therapy data focusing on E+P and its association with breast cancer to set the stage, the lecture then reviewed our newly published data that progestins expand breast cancer stem cells. Finally, the issues of occult or undiagnosed breast cancer in presumably healthy women, and of tumor dormancy in breast cancer survivors, were brought to bear on the discussion. Taken together, these apparently disparate themes allowed me to suggest the idea that systemic progestins have the ability to reawaken cancers that were presumed to be either nonexistent or cured. To avoid this potentially devastating outcome while retaining the benefits of E+P, I advocated the use of local P delivery methods, rather than the currently popular systemic routes.
Horwitz, Kathryn B.
The concept of brain tumor stem cells is gaining increased recognition in neuro-oncology. Until recently, the paradigm of\\u000a a tumor-initiating stem cell was confined to hematopoietic malignancies where the hierarchical lineages of stem progenitor\\u000a cells are well established. The demonstration of persistent stem cells and cycling progenitors in the adult brain, coupled\\u000a with the expansion of the cancer stem cell
Georgia Panagiotakos; Viviane Tabar
The two most basic properties of stem cells are the capacities to self-renew and to differentiate into multiple cell or tissue\\u000a types (1–3). Generally, stem cells are categorized as one of three types: embryonic stem cells (ES), embryonic germ cells (EG), or adult\\u000a stem cells. ES cells are derived from the inner cell mass of the blastula (Fig. 1). They
Kathy E. Mitchell
Stem cells have the capacity for self renewal and undergo multilineage differentiation. Stem cells isolated from both blastocysts and adult tissues represent valuable sources of cells for applications in cell therapy, drug screening and tissue engineering. While expanding stem cells in culture, it is critical to maintain their self?renewal and differentiation capacity. In generating particular cell types for specific applications,
Gargi Seth; Catherine M. Verfaillie
In recent years, clinical trials with stem cells have taken the emerging field in many new directions. While numerous teams continue to refine and expand the role of bone marrow and cord blood stem cells for their vanguard uses in blood and immune disorders, many others are looking to expand the uses of the various types of stem cells found in bone marrow and cord blood, in particular mesenchymal stem cells, to uses beyond those that could be corrected by replacing cells in their own lineage. Early results from these trials have produced mixed results often showing minor or transitory improvements that may be attributed to extracellular factors. More research teams are accelerating the use of other types of adult stem cells, in particular neural stem cells for diseases where beneficial outcome could result from either in-lineage cell replacement or extracellular factors. At the same time, the first three trials using cells derived from pluripotent cells have begun.
Human skeletal muscle contains an accessible adult stem-cell compartment in which differentiated myofibers are maintained and replaced by a self-renewing stem cell pool. Previously, studies using mouse models have established a critical role for resident stem cells in skeletal muscle, but little is known about this paradigm in human muscle. Here, we report the reproducible isolation of a population of
Yan Wei; Yuan Li; Chao Chen; Katharina Stoelzel; Andreas M. Kaufmann; Andreas E. Albers
\\u000a Stem cells are unspecialized cells that can differentiate to generate more specialized cell types responsible for tissue-specific\\u000a function. During development, the differentiation of pluripotent embryonic stem cells leads to the production of specialized\\u000a somatic cells that are ultimately responsible for the structure and function of all adult tissues and organs. “Naturally”\\u000a pluripotent cells exist only at the earliest stages of
Kah Yong Tan; Francis S. Kim; Amy J. Wagers; Shane R. Mayack
The ability of stem cells to self-renew and to replace mature cells is fundamental to ontogeny and tissue regeneration. Stem\\u000a cells of the adult organism can be categorized as mono-, bi-, or multipotent, based on the number of mature cell types to\\u000a which they can give rise. In contrast, pluripotent stem cells of the early embryo have the ability to
M. William Lensch; Laurence Daheron; Thorsten M. Schlaeger
The stem cell concept and asymmetric cell division are best understood in the hematopoietic system. Hematopoietic malignancies\\u000a resemble many of the known normal mature hematopoietic lineages that originate from stem cells. Leukemias in particular, were\\u000a shown to arise from leukemic stem cells. General characteristics of stem cells such as self-renewal, self-protection and proliferative\\u000a quiescence clearly point toward the need for
Angelika M. Burger
Human embryonic stem cells offer the promise of a new regenerative medicine in which damaged adult cells can be replaced with new cells. Research is needed to determine the most viable stem cell lines and reliable ways to promote the differentiation of pluripotent stem cells into specific cell types (neurons, muscle cells, etc.). To create new cell lines, it is necessary to destroy preimplantation blastocysts. This has led to an intense debate that threatens to limit embryonic stem cell research. The profound ethical issues raised call for informed, dispassionate debate.
Fischbach, Gerald D.; Fischbach, Ruth L.
Stem cells are a population of undifferentiated cells characterized by the ability to extensively proliferate (self-renewal), usually arise from a single cell (clonal), and differentiate into different types of cells and tissue (potent). There are several sources of stem cells with varying potencies. Pluripotent cells are embryonic stem cells derived from the inner cell mass of the embryo and induced pluripotent cells are formed following reprogramming of somatic cells. Pluripotent cells can differentiate into tissue from all 3 germ layers (endoderm, mesoderm, and ectoderm). Multipotent stem cells may differentiate into tissue derived from a single germ layer such as mesenchymal stem cells which form adipose tissue, bone, and cartilage. Tissue-resident stem cells are oligopotent since they can form terminally differentiated cells of a specific tissue. Stem cells can be used in cellular therapy to replace damaged cells or to regenerate organs. In addition, stem cells have expanded our understanding of development as well as the pathogenesis of disease. Disease-specific cell lines can also be propagated and used in drug development. Despite the significant advances in stem cell biology, issues such as ethical controversies with embryonic stem cells, tumor formation, and rejection limit their utility. However, many of these limitations are being bypassed and this could lead to major advances in the management of disease. This review is an introduction to the world of stem cells and discusses their definition, origin, and classification, as well as applications of these cells in regenerative medicine. PMID:23257690
Kolios, George; Moodley, Yuben
This project aims to identify adult prostate stem cells, using tissue recombination techniques. To date, we have initiated studies utilizing mouse and human embryonic stem (ES) cells as outlined in the original statement of work. We have made progress tow...
The current status of knowledge about mitochondrial properties in mouse, monkey and human embryonic, adult and precursor stem cells is discussed. Topics include mitochondrial localization patterns, oxygen consumption and ATP content in cells as they relate to the maintenance of stem cell properties and subsequent differentiation of stem cells into specific cell types. The significance of the perinuclear arrangement of mitochondria, which may be a characteristic feature of stem cells, as well as the expression of mitochondrial DNA regulatory proteins and mutations in the mitochondrial stem cell genome is also discussed.
Lonergan, Thomas; Bavister, Barry; Brenner, Carol
Stem cells have offered much hope by promising to greatly extend the numbers and range of patients who could benefit from transplants, and to provide cell replacement therapy to treat debilitating diseases such as diabetes, Parkinson's and Huntington's disease. The issue of stem cell research is politically charged, prompting biologists to begin engaging in ethical debates, and generating in the
Terminal heart failure is characterized by a significant loss of cardiac myocytes. Stem cells represent a possibility for\\u000a replacing these lostmyocytes but the question of which stem cells are most ideally suited for cell transplantation therapies\\u000a is still being addressed. Here, we consider human embryonic stem cells (HESC), derived from human embryos in this context.We\\u000a review the methods used to
R. Passier; C. Denning; C. Mummery
Stem cell-based therapy holds great promise for the treatment of human diseases attributable to the loss or dysfunction of\\u000a a single cell type. However, before stem cells can be used clinically, their safety and efficacy must be clearly established.\\u000a This is particularly important for endocrine applications in which hormone replacement treatments are available. Indeed, new\\u000a stem cell-based treatments must meet
Linda B. Lester; K. Y. Francis Pau; Don P. Wolf
Stem cell therapy based on the safe and unlimited self-renewal of human pluripotent stem cells is envisioned for future use\\u000a in tissue or organ replacement after injury or disease. A gradual decline of regenerative capacity has been documented among\\u000a the adult stem cell population in some body organs during the aging process. Recent progress in human somatic cell nuclear\\u000a transfer
Jan O. Nehlin; Torben Barington
This Comment highlights the recent federal funding setbacks in the biotechnology industry and considers the resulting challenges to future research collaboration. After providing a historical background to stem cell technology, Mr. Fleis examines the passionately opposed public responses to the technology's use of embryos and to its future applications. Fleis continues by noting past legislative initiatives that have accelerated the
Patrick J. Fleis
Evidence has accumulated that cancer develops from a population of quiescent tissue committed\\/pluripotent stem cells (TCSC\\/PSC) or cells developmentally closely related to them that are distributed in various organs. To support this notio n, stem cells (SC) are long lived cells and thus may become the subject of accumulating mutations that are crucial for initiation\\/progression of cancer. More important, they
Mariusz Z. Ratajczak
Human embryonic stem cells hold great promise in furthering our treatment of disease and increasing our understanding of early development. This chapter describes protocols for the derivation and maintenance of human embryonic stem cells. In addition, it summarizes briefly several alternative methods for the culture of human embryonic stem cells. Thus, this chapter provides a good starting point for researchers
Hidenori Akutsu; Chad A. Cowan; Douglas Melton
\\u000a Stem cells are functionally defined as long-lived cells that can both self-renew and differentiate into multiple cell types.\\u000a Embryonic stem cells, considered totipotent cells, give rise to all embryonic tissue layers and, consequently, all tissue\\u000a types. Hematologists\\/oncologists are perhaps most familiar with hematopoietic stem cells (HSCs): the single pluripotent cell\\u000a that can give rise to all lymphoid, myeloid and erythroid
Elizabeth O. Hexner; Stephen G. Emerson
Stem cells are characterized by their dual ability to reproduce themselves (self-renew) and specialize (differentiate), yielding a plethora of daughter cells that maintain and regenerate tissues. In contrast to their embryonic counterparts, adult stem cells retain their unique functions only if they are in intimate contact with an instructive microenvironment, termed stem cell niche. In these niches, stem cells integrate a complex array of molecular signals that, in concert with induced cell-intrinsic regulatory networks, control their function and balance their numbers in response to physiologic demands. This progress report provides a perspective on how advanced materials technologies could be used (i) to engineer and systematically analyze specific aspects of functional stem cells niches in a controlled fashion in vitro and (ii) to target stem cell niches in vivo. Such “artificial niches” constitute potent tools for elucidating stem cell regulatory mechanisms with the capacity to directly impact the development of novel therapeutic strategies for tissue regeneration.
Lutolf, Matthias P.; Blau, Helen M.
Human embryonic stem (hES) cells have traditionally been cultured in medium containing fetal calf serum (FCS) and mouse fibroblasts as feeder cells. The use of animal derived materials carries a risk of transmitting animal pathogens, and they are not optimal in cultures aimed at cell transplantation in humans. This technical study aiming at facilitating IVF units to establish new hES
Heidi Koivisto; Marjukka Hyvärinen; Anne-Marie Strömberg; Jose Inzunza; Eija Matilainen; Milla Mikkola; Outi Hovatta; Heli Teerijoki
Major advances in biological and materials research have created the possibilities for tissue engineering and regenerative\\u000a medicine. Finding the most effective ways of utilising stem cells, of several types, and triggering their differentiatoin\\u000a in a controlled manner will provide cell sources for cell replacement therapy. Materials will be bioresorbable in vivo and bioactive, contributing to differentiation, implantation and long-term engraftment
Robert C. Bielby; Julia M. Polak
Cancers are composed of heterogeneous cell popula- tions ranging from highly proliferative immature cells to more dif- ferentiated cells of various cell lineages. Recent advances in stem cell research have allowed for the demonstration of the existence of cancer stem cells in acute myeloid leukemia, breast cancer, and, most recently, in brain tumors. Each of these has some similarities with
ICHIRO NAKANO; HARLEY I. KORNBLUM
Stem cells are a subcategory of cells designated as “precursor” cells. Precursor cells provide the cellular building blocks\\u000a to maintain the tissues and organs of the body throughout the life-span of an individual. Precursor cells also provide the\\u000a cellular building blocks for tissue replacement and repair following injury. There are three basic categories of precursor\\u000a cells: lineage-uncommitted pluripotent stem cells;
Henry E. Young; Asa C. Black
Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation. The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL-3, IL-6, IL-11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy. PMID:10372109
Quesenberry, P J; Stewart, F M; Zhong, S; Habibian, H; McAuliffe, C; Reilly, J; Carlson, J; Dooner, M; Nilsson, S; Peters, S; Stein, G; Stein, J; Emmons, R; Benoit, B; Bertoncello, I; Becker, P
This article is concerned with the idea that neural precursor cells in vertebrates can self-renew and give rise to all cell types within the nervous system. Supportive evidence for this notion of neural stem cells comes from clonal analyses undertaken both in vivo and in vitro. Neural stem cells also give rise to other cells in the body, including skin
Mark Murphy; Kate Reid; Renée Dutton; Gordon Brooker; Perry F Bartlett
Transplanting embryonic stem cells from embryo into adult as a means of rejuvenating diseased cells, tissues, and organs poses ethical and moral challenges. In recent years, stem cell-derived nerve and glandular tissue has been transplanted into the brains and pancreas of Parkinson's disease and diabetes patients, respectively, with mixed results. This chapter provides background information on stem cell research, the future treatment of Parkinson's disease, and the controversy surrounding this sensitive issue.
The stem cell story begins with the recognition of the regenerative powers of the head of the Lernean Hydra and the human\\u000a liver (Prometheus) by the ancient Greeks. In modern times, the adult human stem cell has been epitomized by the hematopoietic\\u000a stem cell in the bone marrow. More recently, bone marrow derived cells were reported to contribute to nonhematopoietic
Alexandros Spyridonidis; Tina Tomann; Robert Zeiser; Marie Follo; Yannis Metaxas; Jürgen Finke
The tremendous capacity of bone to regenerate is indicative of the presence of stem cells with the capability, by definition,\\u000a to self-renew as well as to give rise to daughter cells. These primitive progenitors, termed mesenchymal stem cells or bone\\u000a marrow stromal stem cells, exist postnatally, and are multipotent with the ability to generate cartilage, bone, muscle, tendon,\\u000a ligament, and
Richard O. C. Oreffo; Cyrus Cooper; Christopher Mason; Mark Clements
Bone marrow-derived multipotent stem and stromal cells (MSCs) are likely candidates for cell-based therapies for various conditions\\u000a including skeletal disease. Advancement of these therapies will rely on an ability to identify, isolate, manipulate, and deliver\\u000a stem cells in a safe and effective manner. Although it is clear that physical signals affect tissue morphogenesis, stem cell\\u000a differentiation, and healing processes, integration
Alesha B. Castillo; Christopher R. Jacobs
Stem cells, which have a great capacity for self-renewal and can differentiate into at least one committed cell type, exist\\u000a in embryonic and adult organisms of many phyla. Although stem cells of various types from mice and other lower organisms have\\u000a been studied for many years, it was not until the derivation of stem cell lines from human embryos in
Victoria L. Browning; Jon S. Odorico
Satellite cells are myogenic stem cells responsible for the post-natal growth, repair and maintenance of skeletal muscle. This review focuses on the basic biology of the satellite cell with emphasis on its role in muscle repair and parallels between embryonic myogenesis and muscle regeneration. Recent advances have altered the long-standing view of the satellite cell as a committed myogenic stem
Jennifer CJ Chen; David J Goldhamer
Recent progress in deriving human embryonic stem (hES) cells and defining their capacity to differentiate has inspired hope that they could become a source of replacement cells for damaged or diseased tissues. We review the immunological barriers to transplanting hES cells and consider several potential solutions, including stem-cell banking, modification of the immunogenicity of donor cells and induction of tolerance
Eleanor M. Bolton; Roger A. Pedersen; J. Andrew Bradley
Advances in our understanding of stem cells in the gastrointestinal tract include the identification of molecular markers of stem and early progenitor cells in the small intestine. Although gastric epithelial stem cells have been localized, little is known about their molecular biology. Recent reports describe the use of inducible Cre recombinase activity to indelibly label candidate stem cells and their progeny in the distal stomach, (ie, the antrum and pylorus). No such lineage labeling of epithelial stem cells has been reported in the gastric body (corpus). Among stem cells in the alimentary canal, those of the adult corpus are unique in that they lie close to the lumen and increase proliferation following loss of a single mature progeny lineage, the acid-secreting parietal cell. They are also unique in that they neither depend on Wnt signaling nor express the surface marker Lgr5. Because pathogenesis of gastric adenocarcinoma has been associated with abnormal patterns of gastric differentiation and with chronic tissue injury, there has been much research on the response of stomach epithelial stem cells to inflammation. Chronic inflammation, as induced by infection with Helicobacter pylori, affects differentiation and promotes metaplasias. Several studies have identified cellular and molecular mechanisms in spasmolytic polypeptide–expressing (pseudopyloric) metaplasia. Researchers have also begun to identify signaling pathways and events that take place during embryonic development that eventually establish the adult stem cells to maintain the specific features and functions of the stomach mucosa. We review the cytologic, molecular, functional, and developmental properties of gastric epithelial stem cells.
MILLS, JASON C.; SHIVDASANI, RAMESH A.
Satellite cells are myogenic stem cells responsible for the post-natal growth, repair and maintenance of skeletal muscle. This review focuses on the basic biology of the satellite cell with emphasis on its role in muscle repair and parallels between embryonic myogenesis and muscle regeneration. Recent advances have altered the long-standing view of the satellite cell as a committed myogenic stem cell derived directly from the fetal myoblast. The experimental basis for this evolving perspective will be highlighted as will the relationship between the satellite cell and other newly discovered muscle stem cell populations. Finally, advances and prospects for cell-based therapies for muscular dystrophies will be addressed.
Chen, Jennifer CJ; Goldhamer, David J
Investors in any new technology are concerned to protect their investment, a key part of such protection being the availability of patent protection. Stem cells, human embryonic stem cells in particular, are a highly controversial area, and this controversy extends to the patenting of stem cells. In this article, the legal issues affecting patenting of stem cell technology in the USA and Europe are reviewed. The types of patents that have been granted are also considered, as an illustration of the protection that can be obtained. Finally, the overall trends in patent filings are discussed, to identify key aspects of the patent landscape. PMID:17465737
The potential clinical use of stem cells for cell transplantation therapies to replace defective genes in myopathies is an area of intense investigation. Precursor cells derived from non-muscle tissue with myogenic potential have been identified in many tissues, including bone marrow and dermis, although the status of these putative stem cells requires clarification. The incorporation of circulating bone-marrow derived stem
Jason D. White; Miranda D. Grounds
Generation of human embryonic stem cell lines is one of the most important achievements in biological science in the 20th\\u000a century. It has excited a wide scientific and social response, as embryonic stem cells (ESC) may, in the future, be regarded\\u000a as an unlimited source of transplantation materials for replacement cell therapy. ESC lines are derived, cultured, inner cell\\u000a mass
N. N. Nikolskii; I. A. Gabai; N. V. Somova
Human embryonic stem cells (HESC) are pluripotent stem cells isolated from the inner cell mass of human blastocysts. With\\u000a the first successful culturing of HESC, a new era of regenerative medicine was born. HESC can differentiate into almost any\\u000a cell type and, in the future, might replace solid organ transplantation and even be used to treat progressive degenerative\\u000a diseases such
Karl-Henrik Grinnemo; Christer Sylvén; Outi Hovatta; Göran Dellgren; Matthias Corbascio
Stem cells are currently in the news for two reasons: the successful cultivation of human embryonic stem cell lines and reports that adult stem cells can differentiate into developmentally unrelated cell types, such as nerve cells into blood cells. Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified. Certain aspects of the stem cell microenvironment, or niche, are conserved between tissues, and this can be exploited in the application of stem cells to tissue replacement therapy.
Watt, Fiona M.; Hogan, Brigid L. M.
The purpose of this essay is to stimulate academic discussion about the ethical justification of using human primordial stem cells for tissue transplantation, cell replacement, and gene therapy. There are intriguing alternatives to using embryos obtained from elective abortions and in vitro fertilisation to reconstitute damaged or dysfunctional human organs. These include the expansion and transplantation of latent adult progenitor cells. Key Words: Primordial stem cell research • embryonic stem cells • pluripotent stem cells • embryo research
Stem cell research is a new field that is advancing at an incredible pace with new discoveries being reported from all over the world. Scientists have for years looked for ways to use stem cells to replace cells and tissues that are damaged or diseased. Stem cells are the foundation cells for every organ, tissue, and cell in the body. Stem cells are undifferentiated, "blank" cells that do not yet have a specific function. Under proper conditions, stem cells begin to develop into specialized tissues and organs. They are self-sustaining and can replicate themselves for long periods of time. Embryonic stem cells are pluripotent cells, isolated from the inner cell mass of the blastocyst-stage mammalian embryo. They have the ability to differentiate into several somatic or somatic-like functional cells such as neurons, hepatocytes, cardiomyocytes, and others. Adult stem cells are specialized cells found within many tissues of the body where they function in tissue homeostasis and repair. They are precursor cells capable of differentiation into several different cells. The knowledge of stem cells from various sources offered a new hope for the treatment of various diseases. PMID:17445575
Aejaz, H M; Aleem, A K; Parveen, N; Khaja, M N; Narusu, M Lakshmi; Habibullah, C M
Terminally differentiated adult cardiomyocytes have limited regenerative capacity and therefore any significant cell loss may result in the development of progressive heart failure. Cell replacement therapy is a promising new approach for myocardial repair but has been limited by the paucity of cell sources for functional human cardiomyocytes. The recent establishment of the human pluripotent embryonic stem (ES) cell lines
Izhak Kehat; Lior Gepstein
The "mesenchymal stem cells (MSCs)" are cells adherent in the bone marrow, which can be isolated to induce differentiation. In contrast to the "embryonic stem cells" whose goal is to develop a new organism, the "MSC adult stem cells" can participate in tissue growth and repair throughout postnatal life. Addition of 5-azacytidine to MSCs in vitro induces the gradual increase in cellular size and begins spontaneous beatings, thereafter differentiating into cardiomyocytes. The "Methods" and "Protocols" to induce structural and functional maturations of MSCs, thus to achieve "Cellular Cardiomyoplasty," are described. With appropriate media, differentiations of MSCs to various kinds of cells such as chondrocytes, osteocytes, and adipocytes are also achievable. PMID:23807784
Duong, Minh Ngoc; Ma, Yu-Ting; Chiu, Ray C J
This review discusses the various regulatory characteristics of microRNAs that are capable of generating widespread changes in gene expression via post translational repression of many mRNA targets and control self-renewal, differentiation and division of cells. It controls the stem cell functions by controlling a wide range of pathological and physiological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis and metastasis. Through either mRNA cleavage or translational repression, miRNAs alter the expression of their cognate target genes; thereby modulating cellular pathways that affect the normal functions of stem cells, turning them into cancer stem cells, a likely cause of relapse in cancer patients. This present review further emphasizes the recent discoveries on the functional analysis of miRNAs in cancer metastasis and implications on miRNA based therapy using miRNA replacement or anti-miRNA technologies in specific cancer stem cells that are required to establish their efficacy in controlling tumorigenic potential and safe therapeutics.
Stem cell research is now a very broad field encompassing cells derived from all stages of life from the embryonic stem cells of the early blastocyst through to the adult stem cells of many tissues of the body. Adult stem cells from a variety of tissues are proving to be pluripotent and can differentiate into cell types different from the
A. Mackay-Sim; P. Silburn
\\u000a Stem cells can be isolated from a variety of sources and they are typically classified based on their tissue of origin. Embryonic\\u000a stem cells are, as the name indicates, derived from the inner cell mass of pre-implantation stage blastocysts at day 5–7 post\\u000a fertilization. These cells possess qualities such as pluripotency and a seemingly limitless capacity to proliferate in vitro
Mikael C. O. Englund; Peter Sartipy; Johan Hyllner
The dogma that solid tumors are composed of tumor cells that all share the same ability to produce proliferating daughter\\u000a cells has been challenged in recent years. There is growing evidence that many adult tissues contain a set of tissue stem\\u000a cells, which might undergo malignant transformation while retaining their stem cell characteristics. These include the ability\\u000a of indefinite self-renewal
Christian Nern; Daniel Sommerlad; Till Acker; Karl H. Plate
The two most promising practical applications of human stem cells are cellular replacement therapies in human disease and toxicological screening of candidate drug molecules. Both require a source of human stem cells that can be isolated, purified, expanded in number and differentiated into the cell type of choice in a controlled manner. Currently, uses of both embryonic and adult stem
Tiina Matikainen; Jarmo. Laine
In cycling tissues that exhibit high turnover, tissue maintenance and repair are coordinated by stem cells. But, how frequently stem cells are replaced following differentiation, aging or injury remains unclear. By drawing together the results of recent lineage-tracing studies, we propose that tissue stem cells are routinely lost and replaced in a stochastic manner. We show that stem cell replacement leads to neutral competition between clones, resulting in two characteristic and recurring patterns of clone fate dynamics, which provide a unifying framework for interpreting clone fate data and for measuring rates of stem cell loss and replacement in vivo. Thus, we challenge the concept of the stem cell as an immortal, slow-cycling, asymmetrically dividing cell. PMID:21750026
Klein, Allon M; Simons, Benjamin D
With the development of stem cell technology, stem cell-based therapy for retinal degeneration has been proposed to restore\\u000a the visual function. Many animal studies and some clinical trials have shown encouraging results of stem cell-based therapy\\u000a in retinal degenerative diseases. While stem cell-based therapy is a promising strategy to replace damaged retinal cells and\\u000a ultimately cure retinal degeneration, there are
Ian Yat-Hin Wong; Ming-Wai Poon; Rosita Tsz-Wai Pang; Qizhou Lian; David Wong
Advances in our understanding of stem cells in the gastrointestinal tract include the identification of molecular markers of stem and early progenitor cells in the small intestine. Although gastric epithelial stem cells have been localized, little is known about their molecular biology. Recent reports describe the use of inducible Cre recombinase activity to indelibly label candidate stem cells and their progeny in the distal stomach, (ie, the antrum and pylorus). No such lineage labeling of epithelial stem cells has been reported in the gastric body (corpus). Among stem cells in the alimentary canal, those of the adult corpus are unique in that they lie close to the lumen and increase proliferation following loss of a single mature progeny lineage, the acid-secreting parietal cell. They are also unique in that they neither depend on Wnt signaling nor express the surface marker Lgr5. Because pathogenesis of gastric adenocarcinoma has been associated with abnormal patterns of gastric differentiation and with chronic tissue injury, there has been much research on the response of stomach epithelial stem cells to inflammation. Chronic inflammation, as induced by infection with Helicobacter pylori, affects differentiation and promotes metaplasias. Several studies have identified cellular and molecular mechanisms in spasmolytic polypeptide-expressing (pseudopyloric) metaplasia. Researchers have also begun to identify signaling pathways and events that take place during embryonic development that eventually establish the adult stem cells to maintain the specific features and functions of the stomach mucosa. We review the cytologic, molecular, functional, and developmental properties of gastric epithelial stem cells. PMID:21144849
Mills, Jason C; Shivdasani, Ramesh A
\\u000a Neural stem cells represent a heterogeneous population of mitotically active, self-renewing and multipotent cells of both\\u000a the developing and the adult central nervous system (CNS) showing complex patterns of gene expression that may vary in both\\u000a space and time. Endogenous stem cells residing within CNS germinal niches might concur to nervous system repair owing to their\\u000a ability to drive neurogenesis
Stefano Pluchino; Marco Bacigaluppi; Elena Brini; Erica Butti; Chiara Cossetti; Melania Cusimano; Lucia Zanotti; Gianvito Martino
Institutional achievements in research of low temperature preservation of stem cells derived from fetal and adult sources\\u000a are presented in the report. Special attention is attended to cryopreservation of pretenders on hemopoietic stem cells from\\u000a human cord blood and fetal liver. Examining of viability of cryopreserved with DMSO fetal liver cells of specific phenotype\\u000a by parallel determining with vital dye
Valentin I. Grischenko; Lubov A. Babiychik; Alexander Yu. Petrenko
\\u000a Normal hematopoiesis develops hierarchically from a hematopoietic stem cell, which is defined by both extensive self-renewal\\u000a capacity and multi-lineage potential, i.e. the ability to give rise to fully differentiated cells of all hematopoietic lineages.\\u000a Since leukemia can be considered as malignant hematopoiesis, the existence of a developmental hierarchy in leukemia with a\\u000a malignant stem cell at its apex was postulated
This Web site from the National Institutes of Health (NIH) provides an overview of the activities of an NIH task force established to move the stem cell research agenda forward. The section titled Scientific Research may be of particular interest to researchers in this area. It provides links to the Web sites of stem cell-related research at a number of NIH institutes, as well as an extensive information index, a FAQs page about stem cell research, information on funding opportunities, and much more.
Human and non-human primate embryonic stem (ES) cells are invaluable resources for developmental studies, pharmaceutical research and a better understanding of human disease and replacement therapies. In 1998, subsequent to the establishment of the first monkey ES cell line in 1995, the first human ES cell line was developed. Later, three of the National Institute of Health (NIH) lines (BG01,
Steven L. SticeA; Nolan L. BoydA; Sujoy K. DharaA; Brian A. GerweA; David W. MachacekA; Soojung ShinB
The use of stem cells to generate replacement cells for damaged heart muscle, valves, vessels and conduction cells holds great potential. Recent identification of multipotent progenitor cells in the heart and improved understanding of developmental processes relevant to pluripotent embryonic stem cells may facilitate the generation of specific types of cell that can be used to treat human heart disease.
Deepak Srivastava; Kathryn N. Ivey
Self-renewal in the intestinal epithelia is fueled by a population of undifferentiated intestinal stem cells (ISCs) that give rise to daughter or progenitor cells, which can subsequently differentiate into the mature cell types required for normal gut function. The cellular signals that regulate self-renewal are poorly understood and the factors that mediate the transition from a stem cell to a progenitor cell in the gut are unknown. Recent studies have suggested that ISCs are located either at the crypt base interspersed between the Paneth cells (eg, Lgr-5+ve cells) or at or near position 4 within the intestinal crypt (eg, DCAMKL-1 or Bmi-1+ve cells). This raises the possibility that distinct stem cell regions exist in the crypts and that ISC's state of activation will determine how the self-renewal is regulated in the intestinal tract.
The central dogma in stem cell biology has been that cells isolated from a particular tissue can renew and differentiate into lineages of the tissue it resides in. Several studies have challenged this idea by demonstrating that tissue specific cell have considerable plasticity and can cross-lineage restriction boundary and give rise to cell types of other lineages. However, the lack
Uma Lakshmipathy; Catherine Verfaillie
uman embryonic stem (ES) cells capture the imagination because they are immortal and have an almost unlimited developmental potential (Fig. 1.1: How hESCs are derived). After many months of growth in culture dishes, these remarkable cells maintain the ability to form cells ranging from muscle to nerve to blood — potentially any cell type that makes up the body. The
H. J. Rippon; A. E. Bishop
Individual stem cells are functionally defined by their self-renewal and differentiation potential. Methods for clonal analysis are essential for understanding stem cells, particularly given the increasing evidence for stem-cell heterogeneity. Stem cells reside within complex microenvironments, making single-cell analysis particularly challenging. Furthermore, simultaneous molecular and functional characterization of single stem cells is not trivial. Here we explore clonal assays applied
Kristin Hope; Mickie Bhatia
Studies of the regenerating hematopoietic system have led to the definition of many of the fundamental principles of stem cell biology. Therapies based on a range of tissue stem cells have been widely touted as a new treatment modality, presaging an emerging new specialty called regenerative medicine that promises to harness stem cells from embryonic and somatic sources to provide replacement cell therapies for genetic, malignant, and degenerative conditions. Insights borne from stem cell biology also portend development of protein and small molecule therapeutics that act on endogenous stem cells to promote repair and regeneration. Much of the newfound enthusiasm for regenerative medicine stems from the hope that advances in the laboratory will be followed soon thereafter by breakthrough treatments in the clinic. But how does one sort through the hype to judge the true promise? Are stem cell biologists and the media building expectations that cannot be met? Which diseases can be treated, and when can we expect success? In this review, we outline the realms of investigation that are capturing the most attention, and consider the current state of scientific understanding and controversy regarding the properties of embryonic and somatic (adult) stem cells. Our objective is to provide a framework for appreciating the promise while at the same time understanding the challenges behind translating fundamental stem cell biology into novel clinical therapies. PMID:14633792
Daley, George Q; Goodell, Margaret A; Snyder, Evan Y
Cell replacement using stem cells is a promising therapeutic approach to treat degenerative motor neuron (MN) disorders, such as amyotrophic lateral sclerosis and spinal cord injury. Human bone marrow-derived mesenchymal stem cells (hMSCs) are a desirable cell source for autologous cell replacement therapy to treat nervous system injury due to their plasticity, low immunogenicity, and a lower risk of tumor
Hwan-Woo Park; Jung-Sun Cho; Chul-Kyu Park; Sung Jun Jung; Chang-Hwan Park; Shin-Jae Lee; Seog Bae Oh; Young-Seok Park; Mi-Sook Chang
Stem cells are views from the perspectives of their function, evolution, development, and cause. Counterintuitively, most stem cells may arise late in development, to act principally in tissue renewal, thus ensuring an organisms long-term survival. Surprisingly, recent reports suggest that tissue-specific adult stem cells have the potential to contribute to replenishment of multiple adult tissues. Stem cells are currently in
Timon C. Liu; Rui Duan; Yan Li; Xue-Feng Li; Li-Ling Tan; Songhao Liu
Primary malignant brain cancer, one of the most deadly diseases, has a high rate of recurrence after treatment. Studies in\\u000a the past several years have led to the hypothesis that the root of the recurrence may be brain tumor stem cells (BTSCs), stem-like\\u000a subpopulation of cells that are responsible for propagating the tumor. Current treatments combining surgery and chemoradiotherapy\\u000a could
Cellular senescence processes affecting tissue resident stem cells are considered, at present, an hallmark of both aging and age-related pathologies. Therefore it is mandatory to address this problem with adequate techniques that could highlight the molecular alterations associated with this complex cellular response to stressors. Here we describe methods to characterize cardiac stem cell (CSC) senescence from a molecular and functional standpoint. PMID:23400436
Cesselli, Daniela; D'Aurizio, Federica; Marcon, Patrizia; Bergamin, Natascha; Beltrami, Carlo Alberto; Beltrami, Antonio Paolo
The ocular surface consists of two distinct types of epithelial cells; conjunctival and corneal. Although anatomically continuous, these epithelia comprise two distinct cell populations. Corneal stem cells are located at the limbus. The microenvironment of the limbus is important in maintaining “stemness” of the stem cells and also acts as a barrier to conjunctival epithelial cells preventing them from migration onto the corneal surface.Damage to the limbus results in varying degrees of limbal stem cell deficiency with characteristic clinical features including conjunctivalization of the cornea. Regenerative management of corneal conjunctivalization utilizing stem cells comprises of two approaches; limbal auto- or allografts by using existing stem cells and induction and regeneration of ocular tissues from embryonic stem cells. Herein, we review stem cells and limbal stem cells in particular, types of epithelial cells in the cornea, markers of corneal epithelial cells in different stages, as well as the current approach to corneal epithelial regeneration.
Ebrahimi, Marzieh; Taghi-Abadi, Ehsan; Baharvand, Hossein
Sperm and egg production requires a robust stem cell system that balances self-renewal with differentiation. Self-renewal at the expense of differentiation can cause tumorigenesis, whereas differentiation at the expense of self-renewal can cause germ cell depletion and infertility. In most organisms, and sometimes in both sexes, germline stem cells (GSCs) often reside in a defined anatomical niche. Factors within the niche regulate a balance between GSC self-renewal and differentiation. Asymmetric division of the germline stem cell to form daughter cells with alternative fates is common. The exception to both these tendencies is the mammalian testis where there does not appear to be an obvious anatomical niche and where GSC homeostasis is likely accomplished by a stochastic balance of self-renewal and differentiation and not by regulated asymmetric cell division. Despite these apparent differences, GSCs in all organisms share many common mechanisms, although not necessarily molecules, to guarantee survival of the germline. PMID:21791699
Spradling, Allan; Fuller, Margaret T; Braun, Robert E; Yoshida, Shosei
The dogma that the genesis of new cells is a negligible event in the adult mammalian brain has long influenced our perception and understanding of the origin and development of CNS tumours. The discovery that new neurons and glia are produced throughout life from neural stem cells provides new possibilities for the candidate cells of origin of CNS neoplasias. The
Rossella Galli; Brent A. Reynolds; Angelo L. Vescovi
reversible continuum. This may, in turn, be dependent on shifting chromatin and gene expression with cell cycle transit. If the phenotype of these primitive marrow cells changes from engraftable stem cell to progenitor and back to engraftable stem cell with cycle transit, then this suggests that the identity of the engraft- able stem cell may be partially masked in nonsynchronized
Peter J. Quesenberry; Gerald A. Colvin; Jean-Francois Lambert
The natural replacement of damaged cells by stem cells occurs actively and often in adult tissues, especially rapidly dividing cells such as blood cells. An exciting case in Boston, however, posits a kind of natural stem cell therapy provided to a mother by her fetus—long after the fetus is born. Because there is a profound lack of medical intervention, this
Diabetes is a leading cause of morbidity and mortality worldwide. Complications of diabetes including renal failure, retinopathy, neuropathy, and cardiovascular disease limit both survival and quality of life. Pancreatic transplantation can restore euglycemia thereby stabilizing or even reversing secondary complications of diabetes as well as improving quality of life particularly in patients with labile diabetes. Recent evidence also shows an improved survival in diabetic patients that undergo pancreatic transplantation when combined with a kidney transplant. Pancreatic transplantation should more properly be referred to as beta cell replacement as the field today encompasses both whole organ and islet cell transplantation. We have outlined herein the indications and contraindications to islet or whole organ pancreas transplantation and we have described periprocedure care and short- and long-term prognosis. PMID:15345204
Bigam, David L.; Shapiro, AM James
Stem cells divide by asymmetric division and display different degrees of potency, or ability to differentiate into various specialized cell types. Owing to their unique regenerative capacity, stem cells have generated great enthusiasm worldwide and represent an invaluable tool with unprecedented potential for biomedical research and therapeutic applications. Stem cells play a central role in the understanding of molecular mechanisms regulating tissue development and regeneration in normal and pathological conditions and open large possibilities for the discovery of innovative pharmaceuticals to treat the most devastating diseases of our time. Not least, their intrinsic characteristics allow the engineering of functional tissues for replacement therapies that promise to revolutionize the medical practice in the near future. In this paper, the authors present the characteristics of pluripotent stem cells and new developments of transdifferentiation technologies and explore some of the biomedical applications that this emerging technology is expected to empower.
de Peppo, Giuseppe Maria; Marolt, Darja
The property of pluripotency confers the capacity for differentiation into a large number of cell types including extra-embryonic,\\u000a somatic and germinal cells. During normal development, pluripotency is acquired by the cells of the early embryo, which shortly\\u000a thereafter undergo differentiation, whereas embryonic stem cells (ESCs) uniquely maintain pluripotency while undergoing extensive\\u000a in vitro proliferation. Studies using ESCs have begun to
Ludovic Vallier; Roger A. Pedersen
Cancers comprise heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages.\\u000a In the last decade, several groups have demonstrated the existence of cancer stem cells in both nonsolid solid tumors, including\\u000a some of the brain: glioblastoma multiforme (GBM), medulloblastoma, and ependymoma. These cells, like their normal counterpart\\u000a in homologous tissues, are multipotent, undifferentiated, self-sustaining, yet transformed
Sara G. M. Piccirillo; Elena Binda; Roberta Fiocco; Angelo L. Vescovi; Khalid Shah
Stem cells have been isolated from human embryos, fetal tissue, umbilical cord blood (UCB), and also from ''adult'' sources. Adult stem cells are found in many tissues of the body and are capable of maintaining, generating, and replacing terminally differentiated cells. A source of pluripotent stem cells has been recently identified in UCB that can also differentiate across tissue lineage
Carmella Van De Ven; Daniel Collins; M. Brigid Bradley; Erin Morris; Mitchell S. Cairo; St. Paul
Injury and disease of the spinal cord are generally met with a poor prognosis. This poor prognosis is due not only to the characteristics of the diseases but also to our poor ability to deliver therapeutics to the spinal cord. The spinal cord is extremely sensitive to direct manipulation, and delivery of therapeutics has proven a challenge for both scientists and physicians. Recent advances in stem cell technologies have opened up a new avenue for the treatment of spinal cord disease and injury. Stem cells have proven beneficial in rodent models of spinal cord disease and injury. In these animal models, stem cells have been shown to produce their effect by the dual action of cell replacement and the trophic support of the factors secreted by these cells. In this review we look at the main clinical trials involving stem cell transplant into the spinal cord, focusing on motor neuron diseases and spinal cord injury. We will also discuss the major hurdles in optimizing stem cell delivery methods into the spinal cord. We shall examine current techniques such as functional magnetic resonance imaging guidance and cell labeling and will look at the current research striving to improve these techniques. With all caveats and future research taken into account, this is a very exciting time for stem cell transplant into the spinal cord. We are only beginning to realize the huge potential of stem cells in a central nervous system setting to provide cell replacement and trophic support. Many more trials will need to be undertaken before we can fully exploit the attributes of stem cells.
Stem cells, including mammalian, and particularly primate primordial stem cells (pPSCs) such as human embryonic stem cells (hESCs), hold great promise for restoring cell, tissue, and organ function. However, cultivation of stem cells, particularly undiffe...
X. H. Parson E. Y. Snyder
Stem cells provide an invaluable tool to develop cell replacement therapies for a range of serious disorders caused by cell\\u000a damage or degeneration. Much research in the field is focused on the identification of signals that either maintain stem cell\\u000a pluripotency or direct their differentiation. Understanding how stem cells communicate within their microenvironment is essential\\u000a to achieve their therapeutic potentials.
Raymond C. B. Wong; Martin F. Pera; Alice Pébay
Significant advances have been made in stem cell research over the past decade. A number of nonhematopoietic sources of stem cells (or progenitor cells) have been identified, including endothelial stem cells and neural stem cells. These discoveries have been a major step toward the use of stem cells for potential clinical applications of organ regeneration. Accordingly, kidney regeneration is currently gaining considerable attention to replace kidney dialysis as the ultimate therapeutic strategy for renal failure. However, due to anatomic complications, the kidney is believed to be the hardest organ to regenerate; it is virtually impossible to imagine such a complicated organ being completely rebuilt from pluripotent stem cells by gene or chemical manipulation. Nevertheless, several groups are taking on this big challenge. In this manuscript, current advances in renal stem cell research are reviewed and their usefulness for kidney regeneration discussed. We also reviewed the current knowledge of the emerging field of renal stem cell biology.
Yokoo, Takashi; Matsumoto, Kei; Yokote, Shinya
Satellite cells, localized in the niche between the membrane of muscle fiber and basal lamina that surrounds it, serve as a source of myoblasts that are necessary for both growth and regeneration of skeletal muscle. Apart from their ability to convert into myoblasts, satellite cells are also able to self-renew, thus, they meet requirements for tissue specific, unipotent stem cells. Recently conducted research revealed that population of satellite cells is heterogeneous. The article summarizes current information on biology and characteristics of satellite cells, and also describes models concerning mechanisms of self-renewal and differentiation of satellite cells. Experiments regarding in vitro differentiation of satellite cells into other cell types are also discussed. Moreover, other population of stem cells localized in the muscle are described in this review. PMID:24044285
Archacka, Karolina; Kowalski, Kamil; Brzóska, Edyta
The pandemic of cardiovascular disease is continuously expanding as the result of changing life styles and diets throughout the Old and New World. Immediate intervention therapy saves the lives of many patients after acute myocardial infarction (MI). However, for many this comes at the price of adverse cardiac remodeling and heart failure. Currently, no conventional therapy can prevent the negative aftermath of MI and alternative treatments are warranted. Therefore, cardiac stem cell therapy has been put forward over the past decade, albeit with modest successes. Mesenchymal Stem Cells (MSC) are promising because these are genuine cellular factories of a host of secreted therapeutic factors. MSC are obtained from bone marrow or adipose tissue (ADSC). However, the heart itself also contains mesenchymal- like stem cells, though more difficult to acquire than ADSC. Interestingly, mesenchymal cells such as fibroblasts can be directly or indirectly reprogrammed to all myocardial cell types that require replacement after MI. To date, the paracrine and juxtacrine mechanisms of ADSC and other MSC on vessel formation are best understood. The preconditioning of, otherwise naive, stem cells is gaining more interest: previously presumed deleterious stimuli such as hypoxia and inflammation, i.e. causes of myocardial damage, have the opposite effect on mesenchymal stem cells. MSC gain a higher therapeutic capacity under hypoxia and inflammatory conditions. In this review, mesenchymal stem cells and their working mechanisms are put into the perspective of clinical cardiac stem cell therapy. PMID:23547963
Przybyt, Ewa; Harmsen, Martin C
Much interest and effort has focused on the therapeutic potential of stem cell technology to treat presently intractable diseases. However, this scientific promise has been accompanied by important issues, including ethical hurdles, political policies and dilemmas concerning cell-source selection (embryonic versus adult stem cells). Although the contribution of stem cells to medical research seems enormous, many countries now face complex
Gorka Orive; Rosa M. Hernández; Alicia R. Gascón; Manoli Igartua; José Luis Pedraz
Motor neuron diseases (MNDs) are a group of neurological disorders that selectively affect motor neurons. There are currently\\u000a no cures or efficacious treatments for these diseases. In recent years, significant developments in stem cell research have\\u000a been applied to MNDs, particularly regarding neuroprotection and cell replacement. However, a consistent source of motor neurons\\u000a for cell replacement is required. Human embryonic
M. Nizzardo; C. Simone; M. Falcone; F. Locatelli; G. Riboldi; G. P. Comi; S. Corti
Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.
Lee, KO; Gan, SU; Calne, RY
Stem cells are views from the perspectives of their function, evolution, development, and cause. Counterintuitively, most stem cells may arise late in development, to act principally in tissue renewal, thus ensuring an organisms long-term survival. Surprisingly, recent reports suggest that tissue-specific adult stem cells have the potential to contribute to replenishment of multiple adult tissues. Stem cells are currently in the news for two reasons: the successful cultivation of human embryonic stem cell lines and reports that adult stem cells can differentiate into developmentally unrelated cell types, such as nerve cells into blood cells. The spotlight on stem cells has revealed gaps in our knowledge that must be filled if we are to take advantage of their full potential for treating devastating degenerative diseases such as Parkinsons's disease and muscular dystrophy. We need to know more about the intrinsic controls that keep stem cells as stem cells or direct them along particular differentiation pathways. Such intrinsic regulators are, in turn, sensitive to the influences of the microenvironment, or niche, where stem cells normally reside. Both intrinsic and extrinsic signals regular stem cell fate and some of these signals have now been identified. Vacek et al and Wang et al have studied the effect of low intensity laser on the haemopoietic stem cells in vitro. There experiments show there is indeed the effect of low intensity laser on the haemopoietic stem cells in vitro, and the present effect is the promotion of haemopoietic stem cells proliferation. In other words, low intensity laser irradiation can act as an extrinsic signal regulating stem cell fate. In this paper, we study how low intensity laser can be used to regulate stem cell fate from the viewpoint of collective phototransduction.
Liu, Timon C.; Duan, Rui; Li, Yan; Li, Xue-Feng; Tan, Li-Ling; Liu, Songhao
Recent studies have indicated that bone marrow stem cells are capable of generating muscle, cardiac, hepatic, renal, and bone cells. Purified hematopoietic stem cells have generated cardiac and hepatic cells and reversed disease manifestations in these tissues. Hematopoietic stem cells also alter phenotype with cell cycle transit or circadian phase. During a cytokine stimulated cell cycle transit, reversible alterations of differentiation and engraftment occur. Primitive hematopoietic stem cells express a wide variety of adhesion and cytokine receptors and respond quickly with migration and podia extensions on exposure to cytokines. These data suggest an "Open Chromatin" model of stem cell regulation in which there is a fluctuating continuum in the stem cell/progenitor cell compartments, rather than a hierarchical relationship. These observations, along with progress in using low dose treatments and tolerization approaches, suggest many new therapeutic strategies involving stem cells and the creation of a new medical specialty; stemology. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6
Quesenberry, Peter J.; Colvin, Gerald A.; Lambert, Jean-Francois; Frimberger, Angela E.; Dooner, Mark S.; Mcauliffe, Christina I.; Miller, Caroline; Becker, Pamela; Badiavas, Evangelis; Falanga, Vincent J.; Elfenbein, Gerald; Lum, Lawrence G.
This review is the second in a series of four devoted to the analysis of recent studies on stem cells. The first considered embryo stem cells (ES). This review covers bone marrow stem cells. They are analysed initially in a historical perspective, and then in relation to foundation studies in the later 20th century before a detailed analysis is presented
... BD™ Stem Cell Enumeration Kit. Applicant: BD Biosciences. 510(k) number: BK110037. Product: BD™ Stem Cell Enumeration Kit. ... More results from www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts
This review is the second in a series of four devoted to the analysis of recent studies on stem cells. The first considered embryo stem cells (ES). This review covers bone marrow stem cells. They are analysed initially in a historical perspective, and then in relation to foundation studies in the later 20th century before a detailed analysis is presented on very recent studies. Methods of identifying, culturing, expanding and grafting stem cells are described, including the separation of haemopoietic and mesenchyme cell lines (HSC and MSC) and recent more detailed analyses using numerous CD and other markers to identify very small subsets of stem cells such as multipotent adult progenitor cells (MAPC) and bone marrow stromal stem cells (BMSSC) from MSC. Queries arising on the immense potential of these stem cell lines due to the discovery of epigentic factors and cell fusions influencing their development and potency are described. A section on cord blood stem cells is followed by a detailed discussion on the modern situation regarding the clinical use of stem cells, its recent setbacks due to epigenetic factors, different approaches to the discovery of a highly multipotent bone marrow stem cell, and a brief description of embryological approaches to identifying the basic bone marrow stem cell in very early mammalian embryos. PMID:15588475
Edwards, R G
Breast cancer stem cells (BCSCs) constitute a subpopulation of tumor cells that express stem cell-associated markers and have a high capacity for tumor generation in vivo. Identification of BCSCs from tumor samples or breast cancer cell lines has been based mainly on CD44+/CD24?/low or ALDH+ phenotypes. BCSCs isolation has allowed the analysis of the molecular mechanisms involved in their origin, self-renewal, differentiation into tumor cells, resistance to radiation therapy and chemotherapy, and invasiveness and metastatic ability. Molecular genetic analysis using knockout animals and inducible transgenics have identified NF-?B, c-Jun, p21CIP1, and Forkhead-like-protein Dach1 in BCSC expansion and fate. Clinical analyses of BCSCs in breast tumors have found a correlation between the proportion of BCSCs and poor prognosis. Therefore, new therapies that specifically target BCSCs are an urgent need. We summarize recent evidence that partially explain the biological characteristics of BCSCs.
Velasco-Velazquez, Marco A.; Homsi, Nora; De La Fuente, Marisol; Pestell, Richard G.
The search for sources of stem/progenitor cells the use of which has a potential to affect course of ischemic heart disease and chronic heart failure is conducted nowadays in many countries. Resident cardiac stem cells (CSC) were revealed during recent years on the basis of expression of c-kit, sca-1, MDR1, and islet-1 markers. In vitro experiments demonstrated possibility of their differentiation into cardiomyocytes, smooth muscle cell and endothelial cells. Introduction of CSC in injured myocardium in animals facilitated its partial repair and short term improvement of cardiac function. This holds promise for the use of these cells in the future. In the review we have attempted to summarize literature data on resident CSC and their application for the treatment of heart diseases. PMID:21623726
Dergilev, K V; Rubina, K A; Parfenova, E V
Stem cells characterized by prolonged self- renewal capacity and multipotency offer the opportunity to treat many degenerative disea- ses and replace or restore invalid tissue. Treat- ment strategies might range from transplan- tation of stem cells or their derivatives, to mobilization and manipulation of endogenous stem cells. In theory, stem cells could be col- lected, grown, and stored to provide
Heiko Wurdak; Maurice Kléber; Hye-Youn Lee; Lukas Sommer
Recent seminal discoveries have significantly advanced the field of stem cell research and received worldwide attention. Improvements in somatic cell nuclear transfer (SCNT) technology, enabling the cloning of Dolly the sheep, and the derivation and differentiation of human embryonic stem cells raised hopes that normal cells could be generated to replace diseased or injured tissue. At the same time, in vitro and in vivo studies demonstrated that somatic cells of one tissue are capable of generating cells of another tissue. It was theorized that any cell might be reprogrammed, by exposure to a new environment, to become another cell type. This concept contradicts two established hypotheses: (1) that only specific tissues are generated from the endoderm, mesoderm, and ectoderm and (2) that tissue cells arise from a rare population of tissue-specific stem cells in a hierarchical fashion. SCNT, cell fusion experiments, and most recent gene transfer studies also contradict these hypotheses, as they demonstrate that mature somatic cells can be reprogrammed to regain pluripotent (or even totipotent) stem cell capacity. On the basis of the stem cell theory, hierarchical cancer stem cell differentiation models have been proposed. Cancer cell plasticity is an established phenomenon that supports the notion that cellular phenotype and function might be altered. Therefore, mechanisms of cellular plasticity should be exploited and the clinical significance of the cancer stem cell theory cautiously assessed. PMID:19778860
Stem cells have the ability to differentiate into specific cell types. The 2 defining characteristics of a stem cell are perpetual self-renewal and the ability to differentiate into a specialized adult cell type. There are 2 major classes of stem cells: pluripotent cells, which can become any cell in the adult body, and multipotent cells, which are restricted to becoming a more limited population of cells. Cell sources, characteristics, differentiation, and therapeutic applications are discussed. Stem cells have great potential in tissue regeneration and repair, but much still needs to be learned about their biology, manipulation, and safety before their full therapeutic potential can be achieved. PMID:19242274
Biehl, Jesse K; Russell, Brenda
Cell transplantation is a promising new modality in treating damaged myocardium after myocardial infarction and in preventing postmyocardial infarction LV remodelling. Two strategies are plausible: the first uses adult tissue stem cells to replace the scar tissues and amend the lost myocardium, whilst the second strategy uses embryonic stem cells in an attempt to regenerate myocardium and\\/or blood vessels.
Oon Cheong Ooi; Hamad F. Al Habib; Zakaria A. Almsherqi; Reida M. El Oakley
Unlike any other type of cell, embryonic stem cells have the capacity to develop into any type of tissue in the body. This potential has ignited interest in the scientific community because the ability to produce replacement tissue such as muscle, bone and nervous tissue would revolutionize medicine. However, this research is extremely controversial because embryonic stem cells are taken
Background: Myocardial infarction is the leading cause of heart failure in developed countries, because even the advanced therapeutic measures of today are usually not sufficient to prevent left ventricular remodeling as they fall short of actual replacement of necrotic cardiac myocytes. Recent new insights into stem cell biology have changed our understanding of regenerative activities in the infarcted heart and
Thomas J. Dengler; Hugo A. Katus
\\u000a The growth and differentiation of stem cells are regulated by biochemical and biophysical cues in the extracellular microenvironment.\\u000a Increasing evidences have shown that substrate topography, one of the biophysical properties of the microenvironment, can\\u000a affect stem cell fate, such as the maintenance of embryonic stem cells and the differentiation of adult and embryonic stem\\u000a cells. The underlying mechanism of how
Benjamin K. K. Teo; Soneela Ankam; Evelyn K. F. Yim
\\u000a Advances in stem cell research in recent decades have been aided by progress in the development of novel technologies aimed\\u000a at biological systems. At the same time mimicking stem cell niches in vitro has become crucial for both basic stem cell research\\u000a and the development of innovative therapies based on stem cells. Innovative microscale technologies can contribute to our\\u000a quantitative
Elena Serena; Elisa Cimetta; Camilla Luni; Nicola Elvassore
\\u000a Hydra’s potential immortality and extensive capacity to regenerate and self-renew is due to the presence of three distinct stem\\u000a cell lineages: ectodermal and endodermal epithelial stem cells, and interstitial stem cells. Over the last few years, stem\\u000a cells in Hydra became well-defined in cellular terms of their biology. More recently, efforts using the nearly unlimited potential for tissue\\u000a manipulation combined
Thomas C. G. Bosch
The potential clinical use of stem cells for cell transplantation therapies to replace defective genes in myopathies is an\\u000a area of intense investigation. Precursor cells derived from non-muscle tissue with myogenic potential have been identified\\u000a in many tissues, including bone marrow and dermis, although the status of these putative stem cells requires clarification.\\u000a The incorporation of circulating bone-marrow derived stem
Jason D. White; Miranda D. Grounds
The case lays out the controversies surrounding stem cell research, looking specifically at therapeutic cloning and how the embryos produced in this process are produced solely to be destroyed. Thus, the dilemma of whether it is ethical to take one life to save another and the dilemma surrounding human cloning. This case may be used to portray problems in the
R. Freeman; Will Truslow; Pia Ahmad; Bidham Pamar
\\u000a A tissue-specific stem cell niche functions to direct either self-renewal or differentiation. The niche comprises all local\\u000a cues that can be sensed by the cell including soluble and insoluble signals, physical forces and cell–cell contacts. Approximating\\u000a the stem cell niche through the utilization of biomaterials may give rise to a greater understanding of the biology of the\\u000a stem cell niche
Ge Zhang; Laura J. Suggs
Unraveling the contribution of stem and progenitor cells to blood vessel formation and, reciprocally, the importance of blood vessels to the production and function of stem and progenitor cells, has been a major focus of vascular research over the last decade, but has spawned many controversies. Here I review how vascular stem and progenitor cells contribute both vascular and nonvascular
Victoria L Bautch
Current findings suggest that multipotent stem cells may be suitable for cell replacement therapies in the treatment of neurodegenerative disorders. Embryonic stem (ES) cells are pluripotent cells isolated from the inner cell mass of the preimplantation blastocyst, which give rise to all cells in the organism. Similarly, multipotent stem cells are also able to regenerate, but are believed to have
M. Gerlach; H. Braak; A. Hartmann; W. H. Jost; P. Odin; J. Priller; J. Schwarz
The use of human embryonic stem cells to replace damaged cells and tissues promises future hope for the treatment of many diseases. However, many countries now face complex ethical and legal questions as a result of the research needed to develop these cell-replacement therapies. The challenge that must be met is how to permit research on human embryonic tissue to
John A. Robertson
Scientists have tried for decades to understand cancer development in the context of therapeutic strategies. The realization that cancers may rely on ''cancer stem cells'' that share the self-renewal feature of normal stem cells has changed the perspective with regard to new approaches for treating the disease. In this review, we propose that one of the differences between normal stem
Linheng Li; William B. Neaves
Melanocyte stem cells differ greatly from melanoma stem cells; the former provide pigmented cells during normal tissue homeostasis and repair, and the latter play an active role in a lethal form of cancer. These 2 cell types share several features and can be studied by similar methods. Aspects held in common by both melanocyte stem cells and melanoma stem cells include their expression of shared biochemical markers, a system of similar molecular signals necessary for their maintenance, and a requirement for an ideal niche microenvironment for providing these factors. This review provides a perspective of both these cell types and discusses potential models of stem cell growth and propagation. Recent findings provide a strong foundation for the development of new therapeutics directed at isolating and manipulating melanocyte stem cells for tissue engineering or at targeting and eradicating melanoma specifically, while sparing nontumor cells. PMID:23438380
Lang, Deborah; Mascarenhas, Joseph B; Shea, Christopher R
The present invention provides compositions and methods for the expansion of stem cells and progenitor cells with adiponectin, adiponectin variants, or other molecules that activate adiponectin receptors and signaling, whereby the stem or progenitor cells...
L. DiMascio M. Uqoezwa Q. Wu T. Reya
Postnatal stem cells are present in many adult tissues, and are thought to ensure homoeostasis by replacing functionally declining cells by newly differentiated ones. Postnatal stem cells used as such or after in vitro manipulation hold out strong hopes for reconstructive therapies. For instance, the grafting of native haematopoietic stem cells (HSC) restores haematopoiesis in genetically deficient individuals or in lethally conditioned leukaemic patients, and systemic injection of in vitro amplified mesenchymal stem cells (MSC) induces recovery of bone growth in patients with osteogenesis imperfecta. Moreover, cells differentiated in vitro from postnatal stem cells exhibiting a specific function can also be used for cell therapy. Myeloid dendritic cells (DC) derived from cultures of HSC may induce tumour-specific cytotoxic T lymphocytes to eradicate the tumour via antigen recognition. In addition, long-lived MSC has been engineered to secrete specific proteins coded by a transgene and used as a source of therapeutic molecules in vivo. All these approaches require large quantities of cells that cannot be obtained (with the exception of HSC) directly from the donor. In vitro procedures allowing the production of therapeutic cells from postnatal stem cells are needed and are at present under development. Below we discuss the rationale and methods currently available for generation of therapeutic cells derived from haematopoietic and mesenchymal stem cells. PMID:16826633
Kindler, Vincent; Suva, Domizio; Soulas, Caroline; Chapuis, Bernard
The gastric epithelium is continuously regenerated by gastric stem cells, which give rise to various kinds of daughter cells, including parietal cells, chief cells, surface mucous cells, mucous neck cells, and enteroendocrine cells. The self-renewal and differentiation of gastric stem cells need delicate regulation to maintain the normal physiology of the stomach. Recently, it was hypothesized that cancer stem cells drive the cancer growth and metastasis. In contrast to conventional clonal evolution hypothesis, only cancer stem cells can initiate tumor formation, self-renew, and differentiate into various kinds of daughter cells. Because gastric cancer can originate from gastric stem cells and their self-renewal mechanism can be used by gastric cancer stem cells, we review here how critical signaling pathways, including hedgehog, Wnt, Notch, epidermal growth factor, and bone morphogenetic protein signaling, may regulate the self-renewal and differentiation of gastric stem cells and gastric cancer stem cells. In addition, the precancerous change of the gastric epithelium and the status of isolating gastric cancer stem cells from patients are reviewed.
The identification of cardiac progenitor cells in mammals raises the possibility that the human heart contains a population of stem cells capable of generating cardiomyocytes and coronary vessels. The characterization of human cardiac stem cells (hCSCs) would have important clinical implications for the management of the failing heart. We have established the conditions for the isolation and expansion of c-kit-positive hCSCs from small samples of myocardium. Additionally, we have tested whether these cells have the ability to form functionally competent human myocardium after infarction in immunocompromised animals. Here, we report the identification in vitro of a class of human c-kit-positive cardiac cells that possess the fundamental properties of stem cells: they are self-renewing, clonogenic, and multipotent. hCSCs differentiate predominantly into cardiomyocytes and, to a lesser extent, into smooth muscle cells and endothelial cells. When locally injected in the infarcted myocardium of immunodeficient mice and immunosuppressed rats, hCSCs generate a chimeric heart, which contains human myocardium composed of myocytes, coronary resistance arterioles, and capillaries. The human myocardium is structurally and functionally integrated with the rodent myocardium and contributes to the performance of the infarcted heart. Differentiated human cardiac cells possess only one set of human sex chromosomes excluding cell fusion. The lack of cell fusion was confirmed by the Cre-lox strategy. Thus, hCSCs can be isolated and expanded in vitro for subsequent autologous regeneration of dead myocardium in patients affected by heart failure of ischemic and nonischemic origin.
Bearzi, Claudia; Rota, Marcello; Hosoda, Toru; Tillmanns, Jochen; Nascimbene, Angelo; De Angelis, Antonella; Yasuzawa-Amano, Saori; Trofimova, Irina; Siggins, Robert W.; LeCapitaine, Nicole; Cascapera, Stefano; Beltrami, Antonio P.; D'Alessandro, David A.; Zias, Elias; Quaini, Federico; Urbanek, Konrad; Michler, Robert E.; Bolli, Roberto; Kajstura, Jan; Leri, Annarosa; Anversa, Piero
Recent scientific achievements in cell and developmental biology have provided unprecedented opportunities for advances in biomedical research. The demonstration that fully differentiated cells can reverse their gene expression profile to that of a pluripotent cell, and the successful derivation and culture of human embryonic stem cells (ESCs) have fuelled hopes for applications in regenerative medicine. These advances have been put
Ramiro Alberio; Keith H Campbell; Andrew D Johnson
Over the past few years, new insights have been added to the study of stem cells in the adult lung. The exploration of endogenous lung progenitors as well as the study of exogenously delivered stem cell populations holds promise for advancing our understanding of the biology of lung repair mechanisms. Moreover, it opens new possibilities for the use of stem cell therapy for the development of regenerative medicine approaches for the treatment of lung disease. Here, we discuss the main types of lung epithelial progenitor populations; the potential of endothelial progenitors, mesenchymal stem cells and embryonic stem cells for lung therapy, as well as summarize the cellular mechanisms involved. PMID:23406722
Ardhanareeswaran, Karthikeyan; Mirotsou, Maria
High dose chemo/radiotherapy requiring autologous haemopoietic stem cell support is increasingly used in a variety of malignant disorders. Mobilised peripheral blood stem cells (PBSC) have largely replaced the use of autologous bone marrow due to more rapid haemopoietic reconstitution with less resource use including blood and platelet transfusion requirements. PBSC graft adequacy is monitored by CD34+ cell and granulocyte-monocyte-colony-forming-cell measurements, and thresholds for rapid engraftment have been determined. Studies are in progress to determine the optimal mobilisation regimens that will permit the achievement of the necessary progenitor thresholds with only one or two aphereses. This will facilitate the use of multiple cycles of high dose therapy and possibly the use of PBSC collected by venesection rather than apheresis. PBSC are also increasingly used in the allogeneic setting where specific mobilisation protocols not using cytotoxic drugs are employed. These technical advances will aid the execution of large trials to determine the efficacy of high dose therapy. PMID:9358614
Watts, M J; Linch, D C
Many elderly people worldwide lose the neurosensory part of their ear and turn deaf. Cochlear implants to restore some hearing after neurosensory hearing loss are, at present, the only therapy for these people. In contrast to this therapy, replacement of hair cells via stem cell therapies holds the promise for a cure. We review here current insights into embryonic, adult, and inducible stem cells that might provide cells for seeding the cochlea with the hope of new hair cell formation. We propose a two-step approach using a first set of transcription factors to enhance the generation of inducible pluripotent stem (iPS) cells and a second set of factors to initiate the differentiation of hair cells. Recent evidence regarding ear development and stem cell research strongly suggest that microRNAs will be an important new regulatory factor in both iPS cell formation and differentiation to reprogram cells into hair cells. In addition, we highlight currently insurmountable obstacles to the successful transformation of stem cells into hair cell precursors and their injection into the cochlear canal to replace lost hair cells.
Beisel, Kirk; Hansen, Laura; Soukup, Garrett
In this article, we have reviewed the developments of studies of stem cells therapy for type 1 diabetes since this century. Review of the literature was based on computer searches (PubMed) and our studies. Type 1 diabetes can now be ameliorated by islet transplantation, but this treatment is restricted by the scarcity of islet tissue. Hopes for a limitless supply of a substitute for primary islets of Langerhans and progress in stem cell biology have led to research into the feasibility of stem/progenitor cells to generate insulin-producing cells to use in replacement therapies for diabetes. An increasing body of evidence indicated that, in addition to embryonic stem cells, several potential adult stem/progenitor cells, derived from pancreas, liver, spleen, and bone marrow could differentiate into insulin-producing cells in vitro or in vivo. However, significant controversy currently exists in this field. Moreover, safe suppression of autoimmunity or specific tolerance to auto-antigens for patients with type 1 diabetes must be achieved before this promising new technology can lead to a great progress in clinical practice. To prevent type 1 diabetes through genetic engineering of hematopoietic stem cells represents another new strategy. Much basic research is still required. PMID:17349714
Lü, Ping; Liu, Fang; Yan, Lei; Peng, Tao; Liu, Tao; Yao, Zhong; Wang, Chun-You
The isolation and characterization of mammary stem cells is fundamental to understanding mammary gland development and tissue homeostasis as well as breast oncogenesis. Recent studies have led to the prospective isolation of pluripotential stem cells from the mouse mammary gland through the identification of specific cell-surface markers and transplan- tation of cells into the mammary stromal microenvironment. A single cell
Jane E. Visvader; Geoffrey J. Lindeman
The pandemic of chronic degenerative diseases associated with aging demographics mandates development of effective approaches for tissue repair. As diverse stem cells directly contribute to innate healing, the capacity for de novo tissue reconstruction harbors a promising role for regenerative medicine. Indeed, a spectrum of natural stem cell sources ranging from embryonic to adult progenitors has been recently identified with unique characteristics for regeneration. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the overarching goal of regenerative medicine is to translate stem cell platforms into practice and achieve cures for diseases limited to palliative interventions. Harnessing the full potential of each platform will optimize matching stem cell-based biologics with the disease-specific niche environment of individual patients to maximize the quality of long-term management, while minimizing the needs for adjunctive therapy. Emerging discovery science with feedback from clinical translation is therefore poised to transform medicine offering safe and effective stem cell biotherapeutics to enable personalized solutions for incurable diseases. PMID:19779576
Nelson, Timothy J; Behfar, Atta; Yamada, Satsuki; Martinez-Fernandez, Almudena; Terzic, Andre
The pandemic of chronic degenerative diseases associated with aging demographics mandates development of effective approaches for tissue repair. As diverse stem cells directly contribute to innate healing, the capacity for de novo tissue reconstruction harbors a promising role for regenerative medicine. Indeed, a spectrum of natural stem cell sources ranging from embryonic to adult progenitors has been recently identified with unique characteristics for regeneration. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the overarching goal of regenerative medicine is to translate stem cell platforms into practice and achieve cures for diseases limited to palliative interventions. Harnessing the full potential of each platform will optimize matching stem cell-based biologics with the disease-specific niche environment of individual patients to maximize the quality of long-term management, while minimizing the needs for adjunctive therapy. Emerging discovery science with feedback from clinical translation is therefore poised to transform medicine offering safe and effective stem cell biotherapeutics to enable personalized solutions for incurable diseases.
Nelson, Timothy J.; Behfar, Atta; Yamada, Satsuki; Martinez-Fernandez, Almudena; Terzic, Andre
Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowl- edge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinson's disease is of
Olivier Preynat-Seauve; Pierre R. Burkhard; Jean Villard; Walter Zingg; Nathalie Ginovart; Anis Feki; Michel Dubois-Dauphin; Samia A. Hurst; Alex Mauron; Marisa Jaconi
\\u000a New developments in the field of spermatogonial stem cell (SSC) research have been reviewed. Novel techniques have rendered\\u000a interesting results in studies on SSC kinetics in nonprimate mammals as well as in primates, and the classical views on the\\u000a nature and the behavior of SSC are being challenged. However, no definite conclusions can yet be drawn. Many new proteins\\u000a have
Dirk G. de Rooij
Embryonic stem cells (ESCs) harbor the potential to generate every cell type of the body by differentiation. The use of hESCs holds great promise for potential cell replacement therapies for degenerative diseases including diabetes mellitus. The recently discovered induced pluripotent stem cells (iPSCs) exhibit immense potential for regenerative medicine as they allow the generation of autologous cells tailored to the
Ortwin Naujok; Chris Burns; Peter M Jones; Sigurd Lenzen
Since the discovery of stem cells, scientists have invested tremendous effort in establishing in vitro culture conditions in order to maintain the self-renewal and efficient proliferative capabilities of stem cells by manipulating a va- riety of growth factors. Fibroblast growth factor (FGF) is one of the most common growth factors used to expand stem cells, including human embryonic stem (hES)
The ability of stem cells to differentiate into various different cell types holds great promise for the treatment of irreversible\\u000a tissue damage that occurs in many debilitating conditions. With stem cell research advancing at a tremendous pace, it is becoming\\u000a clear that one of the greatest hurdles to successful stem cell-derived therapies is overcoming immune rejection of the transplant.\\u000a Although
Tracy S. P. Heng; Jarrod A. Dudakov; Danika M. P. Khong; Ann P. Chidgey; Richard L. Boyd
Multiple sclerosis (MS) is a common neurological disease and a major cause of disability, particularly affecting young adults. It is characterized by patches of damage occurring throughout the brain and spinal cord, with loss of myelin sheaths - the insulating material around nerve fibres that allows normal conduction of nerve impulses - accompanied by loss of cells that make myelin (oligodendrocytes). In addition, we now know that there is damage to nerve cells (neurones) and their fibres (axons) too, and that this occurs both within these discrete patches and in tissue between them. The cause of MS remains unknown, but an autoimmune reaction against oligodendrocytes and myelin is generally assumed to play a major role, and early acute MS lesions almost invariably show prominent inflammation. Efforts to develop cell therapy in MS have long been directed towards directly implanting cells capable of replacing lost oligodendrocytes and regenerating myelin sheaths. Accordingly, the advent of techniques to generate large numbers of oligodendrocytes from embryonic stem cells appeared a significant step towards new stem cell treatments for MS; while the emerging consensus that adult stem cells from, for example, the bone marrow had far less potential to turn into oligodendrocytes was thought to cast doubt on their potential value in this disease. A number of scientific and medical concerns, not least the risk of tumour formation associated with embryonic stem cells, have however, prevented any possible clinical testing of these cells in patients. More recently, increasing understanding of the complexity of tissue damage in MS has emphasized that successful cell therapy may need to achieve far more than simply offering a source of replacement myelin-forming cells. The many and varied reparative properties of bone marrow-derived (mesenchymal) stem cells may well offer new and attractive possibilities for developing cell-based treatments for this difficult and disabling condition. PMID:21481041
The cancer stem cell theory postulates that tumors are sustained by a select cell population with specific features, such as self-renewal ability and the capacity to give rise to a heterogeneous mass of tumor cells. The existence of such cells has been demonstrated for glioblastoma, with these cells being referred to as glioma stem cells (GSCs). Glioblastomas are notoriously heterogeneous tumors, however, and the isolation and characterization of their stem cells will require further investigations. Furthermore, the lack of unequivocal markers for GSCs and a partial overlap in characteristics with other cells often lead to confusion. Here, we review the characteristics necessary for a glioma cell to be considered a stem cell, and we adopt our murine glioblastoma model based on genetically modified neural stem cells to illustrate and discuss the GSC concept. PMID:23584571
Sampetrean, Oltea; Saya, Hideyuki
Different types of pluripotent stem cells can be identified and cultured in vitro. Here an overview is presented of the various pluripotent stem cells types. Embryonal carcinoma (EC) cells that have been cultured in vitro provided the groundwork for future pluripotent cell cultures. Conditions established for these cells such as culture on a feeder layer of mouse embryonic fibroblasts and the importance of fetal calf serum were initially also used for the culture of mouse embryonic stem (ES) cells derived from the inner cell masses of blastocysts. Embryonic stem cells derived from human blastocysts were found to require different conditions and are cultured in the presence of activin and basic fibroblast growth factor. Recently pluripotent stem cells have also been derived from mouse peri-implantation epiblasts. Since these epiblast stem cells (EpiSCs) require the same conditions as the human ES cells it has been suggested that human ES cells are more similar to mouse EpiSCs than to mouse ES cells. Pluripotent cell lines have also been derived from migratory primordial germ cells and spermatogonial stem cells. The creation of pluripotent stem cells from adult cells by the introduction of reprogramming transcription factors, so-called induced pluripotent stem (iPS) cells allowed the derivation of patient-specific pluripotent stem cells without the need of creation of a human blastocyst after cloning by somatic cells nuclear transfer. Recently it has become clear however that iPS cells may be quite different to ES cells in terms of epigenetics. PMID:21747344
Roelen, B A J; Chuva De Sousa Lopes, S M
In the adult organism, all tissue renewal and regeneration depends ultimately on somatic stem cells, and the eye is no exception. The importance of limbal stem cells in the maintenance of the corneal epithelium has long been recognised, and such cells are now used clinically for repair of a severely damaged cornea. The slow cycling nature of lens epithelial cells
Mike Boulton; Julie Albon
Human embryonic stem cells originate from the human preimplantation embryo. The derivation of the first human embryonic stem cells was reported in 1998. Since then we have learnt a great deal about how to isolate and culture these cells. Additionally, their stem cell phenotype and differentiation competence have been determined. Although it is expected that many basic biological properties, such as self-renewal and cell specification, are evolutionary conserved, at least from the mouse, we lack significant knowledge about the molecular events that regulate the unique stem cell features of human embryonic stem cells. The pluripotent nature of human embryonic stem cells has attracted great interest in using them as a source of cells and tissues in cell therapy. Recent progress in human somatic cell nuclear transfer suggests that there may be a solution to the immunotolerance problems associated with the use of human embryonic stem cells in cell-replacement therapy. Thus, human embryonic stem cells supply the research community with unique research tools to study basic biological processes in human cells, model human genetic diseases and develop new cell-replacement therapies. PMID:16480446
The aim of developmental biology is to understand how an egg converts itself into a complete organism through the processes of cell differentiation, morphogenesis and size regulation. The principles that have emerged over recent decades include the constancy of the genome in nearly all cells of an individual, the existence of stem cells in many organs and the overwhelming importance of signalling between cells for the determination of their fate. These and other characteristics of development are discussed here in relation to the prospect of achieving cell and tissue correction or replacement with the help of nuclear transplantation and signalling factors. Nuclear transplantation offers a one-step procedure for generating multipotent embryo cells from the cells of an adult tissue such as skin. It should be possible to proliferate the resulting cells as can be done for mouse embryonic stem cells. Embryo cells can be made to differentiate in many directions by exposing them to various agents or to different concentrations of a single factor such as the transforming growth factor beta class signalling molecule activin. The possibility of a cancerous condition being acquired during these experimental manipulations can be guarded against by transfecting cells with a conditional suicide gene. Thus it may be possible to generate replacement cells or tissues from an adult human for transplantation back to the original donor, without the disadvantage of any genetic incompatibility.
The introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathologic heart and opens new options for the treatment of cardiovascular diseases. The feasibility of adult bone marrow autologous and allogenic cell therapy of ischemic cardiomyopathies has been demonstrated in humans. However, many unresolved questions remain to link experimental with clinical observations. The demonstration that the heart is a self-renewing organ and that its cell turnover is regulated by myocardial progenitor cells offers novel pathogenetic mechanisms underlying cardiac diseases and raises the possibility to regenerate the damaged heart. Indeed, cardiac stem progenitor cells (CSPCs) have recently been isolated from the human heart by several laboratories although differences in methodology and phenotypic profile have been described. The present review points to the potential role of CSPCs in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors. PMID:22114897
Frati, C; Savi, M; Graiani, G; Lagrasta, C; Cavalli, S; Prezioso, L; Rossetti, P; Mangiaracina, C; Ferraro, F; Madeddu, D; Musso, E; Stilli, D; Rossini, A; Falco, A; Angelis, A De; Rossi, F; Urbanek, K; Leri, A; Kajstura, J; Anversa, P; Quaini, E; Quaini, F
Summary Niches regulate lineage-specific stem cell self-renewal vs. differentiation in vivo and are comprised of supportive cells and extracellular matrix components arranged in a 3-dimensional topography of controlled stiffness in the presence of oxygen and growth factor gradients. Mimicking stem cell niches in a defined manner will facilitate production of the large numbers of stem cells needed to realize the promise of regenerative medicine and gene therapy. Progress has been made in mimicking components of the niche. Immobilizing cell-associated Notch ligands increased the self-renewal of hematopoietic (blood) stem cells. Culture on a fibrous scaffold that mimics basement membrane texture increased the expansion of hematopoietic and embryonic stem cells. Finally, researchers have created intricate patterns of cell-binding domains and complex oxygen gradients.
Dellatore, Shara M.; Garcia, A. Sofia; Miller, William M.
Stem cells have the ability to self-renew and differentiate into various cell types. Both cell-intrinsic and extrinsic factors may contribute to aging-related decline in stem cell function and loss of stemness. The maintenance of cellular homeostasis requires timely removal of toxic proteins and damaged organelles that accumulate with age or in pathological conditions. Autophagy is one of the main strategies to eliminate unwanted cytoplasmic materials thereby ultimately preventing cellular damage. Here, we shall discuss the accumulating evidence suggesting that autophagy plays a critical role in the homeostatic control of stem cell functions during aging, tissue regeneration, and cellular reprogramming.
Pan, Huize; Cai, Ning; Li, Mo; Liu, Guang-Hui; Izpisua Belmonte, Juan Carlos
Stem cells are being investigated for their potential use in regenerative medicine. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity. These observations fueled an exciting period of discovery and high expectations followed by controversy that emerged from data suggesting cell-cell fusion as an alternate interpretation for transdifferentiation. However, data supporting stem cell plasticity are extensive and cannot be easily dismissed. Myocardial regeneration is perhaps the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes are generated in what was previously considered a postmitotic organ. On the basis of postmortem microscopic analysis, it is proposed that renewal is achieved by stem cells that infiltrate normal and infarcted myocardium. To further understand the role of stem cells in regeneration, it is incumbent on us to develop instrumentation and technologies to monitor myocardial repair over time in large animal models. This may be achieved by tracking labeled stem cells as they migrate into myocardial infarctions. In addition, we must begin to identify the environmental cues that are needed for stem cell trafficking and we must define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will we be able to regulate this process and begin to realize the full potential of stem cells in regenerative medicine. PMID:12480809
Orlic, Donald; Hill, Jonathan M; Arai, Andrew E
From March 1991 through 31st December 2007, 2042 patients underwent stem cell transplantation at the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. These transplantations included 1405 allogeneic stem cell transplantation, 624 autologous stem cell transplantation, and 13 syngeneic stem cell transplantation. Stem cell transplantation was performed for various diseases including acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, thalassemia major, sickle cell thalassemia, sickle cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combine immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. We had 105 cellular therapies for postmyocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, and renal cell carcinoma. About 30 patients were retransplanted in this center. About 74.9% of the patients (1530 of 2042) remained alive between one to 168 months after stem cell transplantation. Nearly 25.1% (512 of 2042) of our patients died after stem cell transplantation. The causes of deaths were relapse, infections, hemorrhagic cystitis, graft versus host disease, and others. PMID:19111033
Ghavamzadeh, Ardeshir; Alimoghaddam, Kamran; Alimogaddam, Kamran; Jahani, Mohammad; Mousavi, Seied Asadollah; Mousavi, Seyed Asadollah; Iravani, Masood; Bahar, Babak; Khodabandeh, Ali; Khatami, Farnaz; Ghaffari, Fatemeh; Jalali, Arash
Mesenchymal stem cells (MSCs) are pluripotent stromal cells that have the potential to give rise to cells of diverse lineages. Interestingly, MSCs can be found in virtually all postnatal tissues. The main criteria currently used to characterize and identify these cells are the capacity for self-renewal and differentiation into tissues of mesodermal origin, combined with a lack in expression of certain hematopoietic molecules. Because of their developmental plasticity, the notion of MSC-based therapeutic intervention has become an emerging strategy for the replacement of injured tissues. MSCs have also been noted to possess the ability to impart profound immunomodulatory effects in vivo. Indeed, some of the initial observations regarding MSC protection from tissue injury once thought mediated by tissue regeneration may, in reality, result from immunomodulation. Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown, these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. This article focuses on recent advances that have broadened our understanding of the immunomodulatory properties of MSC and provides insight as to their potential for clinical use as a cell-based therapy for immune-mediated disorders and, in particular, type 1 diabetes.
Abdi, Reza; Fiorina, Paolo; Adra, Chaker N.; Atkinson, Mark; Sayegh, Mohamed H.
During the last decade it was realized that stem cell-based therapies hold an enormous therapeutic potential, improving the life of patients with conditions ranging from neurodegenerative and traumatic diseases to regenerative medicine requiring replacement of complex structures such as bones and teeth. Based on their ability to regenerate and/or repair damaged tissue and eventually restore organ function, multiple types of stem/progenitor cells have been discovered. In the field of periodontal regeneration and tooth engineering, several types of adult multipotent mesenchymal stem cells from various sources are currently being investigated. These include the bone marrow stromal stem cells (BMSSCs), adipose-derived stromal cells (ADSCs), dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from human exfoliated deciduous teeth (SHEDs), stem cells from the apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), alveolar bone proper-derived stem cells, and gingival stem cells. The potential of these different MSCs as precursors for regenerative purposes in the dental field is discussed in this chapter. PMID:22936399
Fawzy El-Sayed, K M; Dörfer, C; Fändrich, F; Gieseler, F; Moustafa, M H; Ungefroren, H
Teeth exhibit limited repair in response to damage, and dental pulp stem cells probably provide a source of cells to replace those damaged and to facilitate repair. Stem cells in other parts of the tooth, such as the periodontal ligament and growing roots, play more dynamic roles in tooth function and development. Dental stem cells can be obtained with ease, making them an attractive source of autologous stem cells for use in restoring vital pulp tissue removed because of infection, in regeneration of periodontal ligament lost in periodontal disease, and for generation of complete or partial tooth structures to form biological implants. As dental stem cells share properties with mesenchymal stem cells, there is also considerable interest in their wider potential to treat disorders involving mesenchymal (or indeed non-mesenchymal) cell derivatives, such as in Parkinson's disease.
Volponi, Ana Angelova; Pang, Yvonne; Sharpe, Paul T.
The two most promising practical applications of human stem cells are cellular replacement therapies in human disease and toxicological screening of candidate drug molecules. Both require a source of human stem cells that can be isolated, purified, expanded in number and differentiated into the cell type of choice in a controlled manner. Currently, uses of both embryonic and adult stem cells are investigated. While embryonic stem cells are pluripotent and can differentiate into any specialised cell type, their use requires establishment of embryonic stem cell lines using the inner cell mass of an early pre-implantation embryo. As the blastocyst is destroyed during the process, ethical issues need to be carefully considered. The use of embryonic stem cells is also limited by the difficulties in growing large numbers of the cells without inducing spontaneous differentiation, and the problems in controlling directed differentiation of the cells. The use of adult stem cells, typically derived from bone marrow, but also from other tissues, is ethically non-controversial but their differentiation potential is more limited than that of the embryonic stem cells. Since human cord blood, umbilical cord, placenta and amnion are normally discarded at birth, they provide an easily accessible alternative source of stem cells. We review the potential and current status of the use of adult stem cells derived from the placenta or umbilical cord in therapeutic and toxicological applications.
Matikainen, Tiina [Program of Developmental and Reproductive Biology, Biomedicum Helsinki and Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki (Finland); Laine, Jarmo [Stem Cell and Transplantation Services, Finnish Red Cross Blood Service, Kivihaantie 7, FIN 00310, Helsinki (Finland)]. E-mail: email@example.com
The stem cell field in veterinary medicine continues to evolve rapidly both experimentally and clinically. Stem cells are\\u000a most commonly used in clinical veterinary medicine in therapeutic applications for the treatment of musculoskeletal injuries\\u000a in horses and dogs. New technologies of assisted reproduction are being developed to apply the properties of spermatogonial\\u000a stem cells to preserve endangered animal species. The
Lisa A Fortier; Alexander J Travis
Stem cells are characterized by their potential immortality and are capable of self-renewal and differentiation. Stem cells\\u000a are proposed to provide the potential to cure degenerative diseases and to give important clues regarding human development\\u000a and aging. However, stem cell research has evoked enthusiasm and passionate debate regarding the ethics of their use in medicine\\u000a and reproduction. In this article,
Kirk C. Lo; Shannon Whirledge; Dolores J. Lamb
Autologous transplantation of stem cells is a natural phenomenon at birth in mammals via the umbilical cord. Here, we discuss that a delay in the cord clamping may increase stem cell supply to the baby, thereby allowing an innate stem cell therapy that can render acute benefits in the case of neonatal disease, as well as long-term benefits against age-related diseases. PMID:20020331
Sanberg, Paul R; Park, Dong-Hyuk; Borlongan, Cesar V
\\u000a Asymmetric stem cell division is a fundamental process used to generate cellular diversity and to provide a source of new\\u000a cells in developing and adult organisms. Asymmetric stem cell division leads to another stem cell via self-renewal, and a\\u000a second cell type which can be either a differentiating progenitor or a postmitotic cell. Experimental studies in model organisms\\u000a including the
Glycolipids are compounds containing one or more monosaccharide residues bound by a glycosidic linkage to a hydrophobic moiety.\\u000a Because of their expression patterns and the intracellular localization patterns, glycolipids, including stage-specific embryonic\\u000a antigens (SSEA-3, SSEA-4, and possibly SSEA-1) and gangliosides (e.g., GD3, GD2, and A2B5 antigens), have been used as marker\\u000a molecules of stem cells. In this review, I will
Context: Stem cells are undifferentiated cells with the property of self-renewal and give rise to highly specialized cells under appropriate local conditions. The use of stem cells in regenerative medicine holds great promise for the treatment of many diseases, including those of the thyroid gland. Evidence Acquisition: This review focuses on the progress that has been made in thyroid stem cell research including an overview of cellular and molecular events (most of which were drawn from the period 1990–2011) and discusses the remaining problems encountered in their differentiation. Evidence Synthesis: Protocols for the in vitro differentiation of embryonic stem cells, based on normal developmental processes, have generated thyroid-like cells but without full thyrocyte function. However, agents have been identified, including activin A, insulin, and IGF-I, which are able to stimulate the generation of thyroid-like cells in vitro. In addition, thyroid stem/progenitor cells have been identified within the normal thyroid gland and within thyroid cancers. Conclusions: Advances in thyroid stem cell biology are providing not only insight into thyroid development but may offer therapeutic potential in thyroid cancer and future thyroid cell replacement therapy.
Latif, Rauf; Minsky, Noga C.; Ma, Risheng
Stem cells are currently at the center of both controversy and notoriety. The harvest of human embryonic or fetal stem cells, at least with methods available now, necessarily involves the sacrifice of the embryo or fetus. This critical step in the procurement of stem cells has stimulated intense discussion at all levels of academia, government, and society in general. What societal benefits, if any, justify such a strategy for obtaining these stem cells? In other species it has been possible to generate virtually all cell types found in adult organs from embryonic stem cells. This ability has opened endless clinical possibilities for tissue and organ replacement through the transplantation of cells derived from embryonic stem cells. Luckily, there may be an alternative to this ethical dilemma. It is becoming increasingly clear that stem cells exist in many, if not all, adult tissues. Adult stem cells normally replenish tissue cells lost through the wear and tear of aging or damage from injury or disease. With the proper coaxing in tissue culture and when transplanted, these stem cells may regenerate the full repertoire of organotypic cells and thus may therapeutically regenerate tissues in vivo in much the same way as embryonic stem cells do. For several reasons, the best-studied stem cells are those of the blood-forming system. Mature blood cells generally have short functional life spans, usually measured in days, and therefore require replenishment at a steady pace throughout one's lifetime. Stem cells are intimately involved in this renewal and, because of the relative ease of access to the bone marrow, stem cells have been well studied. Second, bone marrow transplantation following radiation or high-dose chemotherapy in the treatment of cancer has fostered research on the basic biology and therapeutic uses of hematopoietic stem cells over the more than 30 years stem cell transplantation has been used clinically. It is my aim to review what is known about the genes controlling hematopoietic stem cell function. Identifying, and ultimately manipulating, the genes that regulate stem cell number, replication rate, and self-renewal capacity may have important clinical benefits. I discuss evidence suggesting that the characterization of least some of these stem cell genes will shed light on mechanisms important in the aging process. I advance the hypothesis that stem cells accumulate cellular damage during aging that diminishes their developmental potency and ability to replenish blood cells, particularly after hematopoietic stress. In this view, the impaired function of stem cells in hematopoietic and in other self-renewing tissues limits the longevity of animals, and perhaps of humans. PMID:12568297
Van Zant, Gary
Cellular and tissue regeneration in the gastrointestinal tract and liver depends on stem cells with properties of longevity, self-renewal and multipotency. Progress in stem cell research and the identification of potential esophageal, gastric, intestinal, colonic, hepatic and pancreatic stem cells provides hope for the use of stem cells in regenerative medicine and treatments for disease. Embryonic stem cells and induced
Michael Quante; Timothy C. Wang
Brain and spinal cord injuries present significant therapeutic challenges. The treatments available for these conditions are largely ineffective, partly due to limitations in directly targeting the therapeutic agents to sites of pathology within the central nervous system (CNS). The use of stem cells to treat these conditions presents a novel therapeutic strategy. A variety of stem cell treatments have been examined in animal models of CNS trauma. Many of these studies have used stem cells as a cell-replacement strategy. These investigations have also highlighted the significant limitations of this approach. Another potential strategy for stem cell therapy utilises stem cells as a delivery mechanism for therapeutic molecules. This review surveys the literature relevant to the potential of mesenchymal stem cells for delivery of therapeutic agents in CNS trauma in humans.
Azari, Michael F; Mathias, Louisa; Ozturk, Ezgi; Cram, David S; Boyd, Richard L; Petratos, Steven
Stem cell leukemia (SCL) protein has been shown to be an essential transcription factor during hematopoietic development in the embryo. In adult hematopoiesis, however, the role for SCL has remained largely unknown, whereas it is expressed in bone marrow hematopoietic stem cells (HSCs). In this study, we performed HSC transplantation and an in vitro HSC differen- tiation assay using retrovirally
Atsushi Kunisato; Shigeru Chiba; Toshiki Saito; Keiki Kumano; Etsuko Nakagami-Yamaguchi; Tomoyuki Yamaguchi; Hisamaru Hirai
Human pluripotent stem cells (PSCs), encompassing embryonic stem cells and induced pluripotent stem cells, proliferate extensively and differentiate into virtually any desired cell type. PSCs endow regenerative medicine with an unlimited source of replacement cells suitable for human therapy. Several hurdles must be carefully addressed in PSC research before these theoretical possibilities are translated into clinical applications. These obstacles are: (1) cell proliferation; (2) cell differentiation; (3) genetic integrity; (4) allogenicity; and (5) ethical issues. We discuss these issues and underline the fact that the answers to these questions lie in a better understanding of the biology of PSCs. To contribute to this aim, we have developed a free online expression atlas, Amazonia!, that displays for each human gene a virtual northern blot for PSC samples and adult tissues (http://www.amazonia.transcriptome.eu).
Ramirez, Jean-Marie; Bai, Qiang; Dijon-Grinand, Marilyne; Assou, Said; Gerbal-Chaloin, Sabine; Hamamah, Samir; Vos, John De
Trophoblast stem cells (TSC) are the precursors of the differentiated cells of the placenta. In the mouse, TSC can be derived from outgrowths of either blastocyst polar trophectoderm (TE) or extraembryonic ectoderm (ExE), which originates from polar TE after implantation. The mouse TSC niche appears to be located within the ExE adjacent to the epiblast, on which it depends for essential growth factors, but whether this cellular architecture is the same in other species remains to be determined. Mouse TSC self-renewal can be sustained by culture on mitotically inactivated feeder cells, which provide one or more factors related to the NODAL pathway, and a medium supplemented with FGF4, heparin, and fetal bovine serum. Repression of the gene network that maintains pluripotency and emergence of the transcription factor pathways that specify a trophoblast (TR) fate enables TSC derivation in vitro and placental formation in vivo. Disrupting the pluripotent network of embryonic stem cells (ESC) causes them to default to a TR ground state. Pluripotent cells that have acquired sublethal chromosomal alterations may be sequestered into TR for similar reasons. The transition from ESC to TSC, which appears to be unidirectional, reveals important aspects of initial fate decisions in mice. TSC have yet to be derived from domestic species in which remarkable TR growth precedes embryogenesis. Recent derivation of TSC from blastocysts of the rhesus monkey suggests that isolation of the human equivalents may be possible and will reveal the extent to which mechanisms uncovered by using animal models are true in our own species. PMID:21106963
Roberts, R Michael; Fisher, Susan J
The Harvard Stem Cell Institute (HSCI) was formed in 2004 to "draw Harvard's resources together by establishing a cooperative community of scientists and practitioners, by developing new ways to fund and support research, and by promoting opportunities for open communication and education." Their website features videos of HSCI scientists speaking about their selected disease programs. Visitors can click on a video as it appears, or they can wait for one of the next videos in the rotation. To read about the disease programs, visitors can click on the "Research" tab near the top of the page, and then select the "Research Programs" link to read about the different programs and the lead researcher. Research programs include the "Blood Disease Program", "Cancer Program", "Cardiovascular Disease Program", "Kidney Disease Program", "Nervous System Diseases Program", and the "Translational Research Program". The "Resources" tab near the top of the page has video of a great series of education sessions that are held quarterly by HSCI, and which address the medical, religious, economic, and public policy concerns that stem cell research presents. There are eight sessions to watch, and each runs longer than an hour, so each topic is covered in exquisite detail.
Recent evidence would suggest that the heart is not a terminally differentiated organ and has the ability to regenerate itself under normal and pathophysiologic conditions. A major effort has been made to identify precursor cells that are capable of differentiating into cell lineages different from their organ of origin. Embryonic stem cells and bone marrow-derived cells (BMCs) have been studied and characterized, and BM precursor cells are currently being utilized as therapy in clinical trials of patients with heart failure of ischemic and nonischemic etiologies. Controversy remains, however, whether BMCs are the best cells to be used for replacement therapy. The existence of a cardiac stem cell (CSC) has also been described, which has the ability to generate new cardiac myocytes and blood vessels, raising the possibility of rebuilding a damaged heart with the organ's own precursor stem cell population. Animal studies have suggested such a possibility, and a clinical trial using CSCs is in progress. This monograph discusses our current understanding of myocardial regeneration and the roles that endogenous and exogenous stem cells may have in the future therapy of cardiovascular disease. PMID:18243902
Leri, Annarosa; Kajstura, Jan; Anversa, Piero; Frishman, William H
Multipotent adult stem cells have many potential therapeutic applications. Our recent findings suggest that hair follicles are a promising source of easily accessible multipotent stem cells. Stem cells in the hair follicle area express the neural stem cell marker nestin, suggesting that hair-follicle stem cells and neural stem cells have common features. Nestin-expressing hair follicle stem cells can form neurons and other cell types, and thus adult hair follicle stem cells could have important therapeutic applications, particularly for neurologic diseases. Transplanted hair follicle stem cells promote the functional recovery of injured peripheral nerve and spinal cord. Recent findings suggest that direct transplantation of hair-follicle stem cells without culture can promote nerve repair, which makes them potentially clinically practical. Human hair follicle stem cells as well as mouse hair follicle stem cells promote nerve repair and can be applied to test the hypothesis that human hair follicle stem cells can provide a readily available source of neurologically therapeutic stem cells. The use of hair follicle stem cells for nerve regeneration overcomes critical problems of embryonic stem cells or induced pluripotent stem cells in that the hair follicle stem cells are multipotent, readily accessible, non-oncogenic, and are not associated with ethical issues. PMID:21036545
Amoh, Yasuyuki; Katsuoka, Kensei; Hoffman, Robert M
Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumors are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs). Understanding how CSCs form and how they contribute to the pathology of breast cancer will greatly aid the pursuit of novel therapies targeted at eliminating these cells. This review will summarize what is currently known about the origins of breast CSCs, their role in disease progression and ways in which they may be targeted therapeutically. PMID:23986719
Owens, Thomas W; Naylor, Matthew J
The mammary gland is a unique organ in that it undergoes most of its development after birth under the control of systemic\\u000a hormones. Whereas in most other organs stem cells divide in response to local stimuli, to replace lost cells, in the mammary\\u000a gland large numbers of cells need to be generated at specific times during puberty, estrous cycles and
Cathrin Brisken; Stephan Duss
Epidermal stem cells sustain the adult skin for a lifetime through self-renewal and the production of committed progenitors. These stem cells generate progeny that will undergo terminal differentiation leading to the development of a protective epidermal barrier. Whereas the molecular mechanisms that govern epidermal barrier repair and renewal have been extensively studied, pathways controlling stem cell differentiation remain poorly understood. Asymmetric cell divisions, small non-coding RNAs (microRNAs), chromatin remodeling complexes, and multiple differentiation factors tightly control the balance of stem and progenitor cell proliferation and differentiation, and disruption of this balance leads to skin diseases. In this review, we summarize and discuss current advances in our understanding of the mechanisms regulating epidermal stem and progenitor cell differentiation, and explore new relationships for maintenance of skin barrier function.
Cangkrama, Michael; Ting, Stephen B.; Darido, Charbel
Recently, there has been growing interest in applying bioprinting techniques to stem cell research. Several bioprinting methods have been developed utilizing acoustics, piezoelectricity, and lasers to deposit living cells onto receiving substrates. Using these technologies, spatially defined gradients of immobilized biomolecules can be engineered to direct stem cell differentiation into multiple subpopulations of different lineages. Stem cells can also be patterned in a high-throughput manner onto flexible implementation patches for tissue regeneration or onto substrates with the goal of accessing encapsulated stem cells of interest for genomic analysis. Here, we review recent achievements with bioprinting technologies in stem cell research, and identify future challenges and potential applications including tissue engineering and regenerative medicine, wound healing, and genomics. PMID:23260439
Tasoglu, Savas; Demirci, Utkan
The discovery of adult stem cells in most adult tissues is the basis of a number of clinical studies that are carried out, with therapeutic use of hematopoietic stem cells as a prime example. Intense scientific debate is still ongoing as to whether adult stem cells may have a greater plasticity than previously thought. Although cells with some features of embryonic stem cells that, among others, express Oct4, Nanog and SSEA1 are isolated from fresh tissue, it is not clear if the greater differentiation potential is acquired during cell culture. Moreover, adult more pluripotent cells do not have all pluripotent characteristics typical for embryonic stem cells. Recently, some elegant studies were published in which adult cells could be completely reprogrammed to embryonic stem cell-like cells by overexpression of some key transcription factors for pluripotency (Oct4, Sox2, Klf4 and c-Myc). It will be interesting for the future to investigate the exact mechanisms underlying this reprogramming and whether similar transcription factor pathways are present and/or can be activated in adult more pluripotent stem cells.
Geraerts, Martine; Verfaillie, Catherine M.
Medicine will be faced with a major challenge in coming years, namely how to treat for tissue dysfunction due to disease and aging There are two basic options: drug therapy and cell therapy. Stem cells have been the subject of intense speculation and controversy for several years, as they open up radically new therapeutic possibilities. Classical drugs can only smoothen consequences of tissue dysfunction, whereas cell therapy has the potential to restore tissue function by providing fresh cells. Cell therapy is totally different from organ transplantation, which can only benefit a limited number of patients. The use of the generic term "stem cells" to designate a whole variety of cell types that are present throughout life, is a source of confusion and ambiguity. It will take years of cognitive research to unravel the molecular mechanisms that govern a stem cell's multi- or totipotent status before we can fully exploit this therapeutic tool to the full. The younger a stem cell the greater its potential and, probably, the more durable its benefits, but the use of embryonic stem cells raises ethical issues. The redundancy or equivalence of diferent categories of cells is another source of controversy, yet researchers must be able to study stem cells in all their diversity, as complementary rather than competitive alternatives, in an acceptable ethical and regulatory environment. We briefly describe the three types of stem cells: pluripotent embryonic stem cells, fetal and adult stem cells, and pluripotent reprogrammed adult somatic cells. Only the former two categories have physiological functions: the first gives rise to tissues and organs while the second maintains tissue function during adulthood PMID:19883007
\\u000a It has been hypothesized for over 40 years that cancers contain the same cell populations as normal tissues: stem cells, proliferating\\u000a transit-amplifying cells, and terminally differentiated (mature cells). The properties of cancer stem cells include the ability\\u000a to transplant the tumor, the ability to grow in vitro and the ability to resist conventional therapies. The idea that cancer\\u000a arose from
Stem cell research is a innovative technology that focuses on using undifferentiated cells able to self-renew through the asymmetrical or symmetrical divisions. Three types of stem cells have been studied in laboratory including embryonic stem cell, adult stem cells and induced pluripotent stem cells. Embryonic stem cells are pluripotent stem cells derived from the inner cell mass and it can give rise to any fetal or adult cell type. Adult stem cells are multipotent, have the ability to differentiate into a limited number of specialized cell types, and have been obtained from the bone marrow, umbilical cord blood, placenta and adipose tissue. Stem cell therapy is the most promising therapy for several degenerative and devastating diseases including digestive tract disease such as liver failure, inflammatory bowel disease, Celiac sprue, and pancreatitis. Further understanding of biological properties of stem cells will lead to safe and successful stem cell therapies. (Korean J Gastroenterol 2011;58: 125-132). PMID:21960099
Seo, Geom Seog
Embryonic cortical neural stem cells are self-renewing progenitors that can differentiate into neurons and glia. We generated neurospheres from the developing cerebral cortex using a mouse genetic model that allows for lineage selection and found that the self-renewing neural stem cells are restricted to Sox2 expressing cells. Under normal conditions, embryonic cortical neurospheres are heterogeneous with regard to Sox2 expression and contain astrocytes, neural stem cells, and neural progenitor cells sufficiently plastic to give rise to neural crest cells when transplanted into the hindbrain of E1.5 chick and E8 mouse embryos. However, when neurospheres are maintained under lineage selection, such that all cells express Sox2, neural stem cells maintain their Pax6+ cortical radial glia identity and exhibit a more restricted fate in vitro and after transplantation. These data demonstrate that Sox2 preserves the cortical identity and regulates the plasticity of self-renewing Pax6+ radial glia cells.
Remboutsika, Eumorphia; Elkouris, Maximilianos; Iulianella, Angelo; Andoniadou, Cynthia L.; Poulou, Maria; Mitsiadis, Thimios A.; Trainor, Paul A.; Lovell-Badge, Robin
This paper discusses the ethical and political issues that stem cell research faces. Stem cell research holds great promise for treating serious diseases but does so by using materials from the very beginning of life. There is a division among different sects of society as some see a important ethical principle being threatened, while others see scientific progress being threatened
Therapies involving adult stem cells are dependent upon sufficient expansion of these cells to repopulate or replace the diseased tissue and are consequently hindered by their relatively quiescent phenotype. Cellular proliferation is governed by the cyclin-dependent kinases, which in a complex with a corresponding cyclin, phosphorylate a number of downstream mediators to drive the cell through the cell cycle. In
M J Boyer; T Cheng
Emerging evidence suggests that cancer stem cells account for the initiation and progression of cancer. While many types of\\u000a cancer stem cells with specific markers have been isolated and identified, a variety of differences among them began to be\\u000a appreciated. Cancer stem cells are hierarchical populations that consist of precancerous stem cells, primary cancer stem cells,\\u000a migrating cancer stem cells
Hai-Guang Liu; Chong Chen; Han Yang; Yi-Fei Pan; Xiao-Hua Zhang
The medical use of low level laser (LLL) irradiation has been occurring for decades, primarily in the area of tissue healing and inflammatory conditions. Despite little mechanistic knowledge, the concept of a non-invasive, non-thermal intervention that has the potential to modulate regenerative processes is worthy of attention when searching for novel methods of augmenting stem cell-based therapies. Here we discuss the use of LLL irradiation as a "photoceutical" for enhancing production of stem cell growth/chemoattractant factors, stimulation of angiogenesis, and directly augmenting proliferation of stem cells. The combination of LLL together with allogeneic and autologous stem cells, as well as post-mobilization directing of stem cells will be discussed.
The issue-focused, peer-reviewed article explains how stem cells have the potential to cure many human diseases because they are: like blank cells - they can become any cell in the human body, enduring - embryos, in particular, can provide an endless supply of stem cells, and regenerative - they can be used as a live source of self-repair.
Lauren Pecorino (University of Greenwich, U.K.;)
The conditioning prior to allogeneic stem cell transplantation was originally designed as a myeloablative conditioning, designed to eliminate malignant or genetically abnormal cells and then use the transplant procedure for rescue of the patients or to replace missing bone marrow products. However, allografts can induce effective graft vs. malignancy effects and can also eliminate undesirable hematopoietic stem cells in patients
I. B. Resnick; M. Y. Shapira; S. Slavin
Regenerative medicine and tissue engineering are searching for a novel stem cell based therapeutic strategy that will allow for efficient treatment or even potential replacement of damaged organs. The pluripotent stem cell (PSC), which gives rise to cells from all three germ lineages, seems to be the most ideal candidate for such therapies. PSC could be extracted from developing embryos.
Mariusz Z. Ratajczak; Ewa K. Zuba-Surma; Marcin Wysoczynski; Wu Wan; Janina Ratajczak; Wojciech Wojakowski; Magda Kucia
Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes, conventional anticancer therapies have to be replaced with specific approaches targeting CSCs. In this review we provide strong support that BMP4 is an innovative therapeutic approach to prevent colon cancer growth increasing differentiation markers expression and apoptosis. Recent data suggest that in colorectal CSCs, protection from apoptosis is achieved by interleukin-4 (IL-4) autocrine production through upregulation of antiapoptotic mediators, including survivin. Consequently, IL-4 neutralization could deregulate survivin expression and localization inducing chemosensitivity of the colon CSCs pool.
Catalano, Veronica; Gaggianesi, Miriam; Spina, Valentina; Iovino, Flora; Dieli, Francesco; Stassi, Giorgio; Todaro, Matilde
The main properties of stem cells include long-term self-renewal and the capacity to give rise to one or more types of differentiated progeny. Recently, much evidence was provided that leukemia and tumor maintenance and growth are sustained by a small proportion of cells exhibiting stem cell properties. In neural tumors, stem cells have been detected in glioblastoma, medulloblastoma and ependymoma.
Silvia K. Nicolis
Human neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders. PMID:23681704
Martínez-Morales, P L; Revilla, A; Ocańa, I; González, C; Sainz, P; McGuire, D; Liste, I
Adult tissue-specific stem cells have the capacity to self-renew and generate functional differentiated cells that replenish lost cells throughout an organism's lifetime. Studies on stem cells from di- verse systems have shown that stem cell function is controlled by extracellular cues from the niche and by intrinsic genetic programs within the stem cell. Here, we review the remarkable progress re-
Linheng Li; Ting Xie
ABSTRACT Human embryonic,stem (hES) cells may potentially revolutionize biomedicine,through their use as a renewable source of cells for regenerative medicine. However, despite much promise the use and derivation of these cells in many countries is ethically challenging. Interestingly, stem cell research in Iran?s R oyan Institute is thriving despite m any challenges and has led to the generation of novel
David W. G. Morrison; Ali Khademhosseini
Summary Very small embryonic-like stem cells (VSELs) isolated from bone marrow (BM) have been reported to be pluripotent. Given their nonembryonic source, they could replace blastocyst-derived embryonic stem cells in research and medicine. However, their multiple-germ-layer potential has been incompletely studied. Here, we show that we cannot find VSELs in mouse BM with any of the reported stem cell potentials, specifically for hematopoiesis. We found that: (1) most events within the “VSEL” flow-cytometry gate had little DNA and the cells corresponding to these events (2) could not form spheres, (3) did not express Oct4, and (4) could not differentiate into blood cells. These results provide a failure to confirm the existence of pluripotent VSELs.
Miyanishi, Masanori; Mori, Yasuo; Seita, Jun; Chen, James Y.; Karten, Seth; Chan, Charles K.F.; Nakauchi, Hiromitsu; Weissman, Irving L.
Stem cell therapy has a place for future application in the treatment of degenerative diseases. Regardless of the origin of the stem cell, when placed within a milieu of inflammatory mediator, they will show varied functions. This re- view focuses on human mesenchymal stem cells (MSCs) and discusses neuronal replacement using multi- and inter- disciplinary approaches. We caution the enthusiasm
Andrew C. Heinrich; Shyam A. Patel; Bobby Y. Reddy; Russell Milton; Pranela Rameshwar
Abnormal endometrial function remains a significant cause of implantation failure, recurrent pregnancy loss, and other pathologies responsible for female infertility. The development of novel therapies to treat infertility due to endometrial dysfunction requires an understanding of the latest advancements in endometrial cell biology, such as the role of endometrial stem cells. The remarkable regenerative capacity of the human endometrium is absolutely essential for successful reproduction and likely requires a population of stem cells in the endometrium. The purpose of this review is to provide an introduction to some of the newest concepts in endometrial stem cell biology.
Morelli, Sara S.; Yi, Pauline; Goldsmith, Laura T.
Advances in our understanding of the biology of stem cells, including neural, hematopoietic and mesenchymal stem cells, have\\u000a opened new avenues for cell-based therapeutic approaches to replace damaged or lost neurons. The mature central nervous system\\u000a (CNS) has traditionally been considered an unfavourable environment for the regeneration of damaged axons or the generation\\u000a of new neurons. The recent realization that
L. Bai; S. L. Gerson; R. H. Miller
Stem cell transplantation consists in the introduction of stem cells or derived products in a diseased organism. Because of\\u000a the differentiation properties of stem cells, the goal is to replace damaged cells or tissues. Numbers of stem cell were identified\\u000a and isolated from embryos, fetuses, or adult organs, harboring different properties, and thus providing multiple strategies\\u000a of regenerative medicine for
Olivier Preynat-Seauve; Karl-Heinz Krause
In today's scenario, medical and dental professionals face a mammoth task while treating perplexing medical situations like organ failure or tissue loss. Though, different strategies exist to replace them, but ideal one is the same natural tissue or organ. In this aspect, stem cells have emerged in a promising way to provide an ideal replacement. There are different types of stem cells starting from the embryonic stage referred to as human embryonic stem cells to adult stem cells. Though in dentistry stem cell research is lagging as compared to the medical field but still a lot progress has been achieved in recent years. The stem cells have been isolated from dental pulp, human exfoliated deciduous teeth, and apical papilla and so on. These stem cells have provided exciting results like dentin-pulp regeneration, periodontal regeneration but ambiguity still prevails. As a result, much has to be further researched before its clinical application becomes a reality. Hence, these stem cells opened a new avenue in the field of regenerative dentistry.
Chopra, Hitesh; Hans, Manoj Kumar; Shetty, Shashit
Pluripotent stem cells hold enomous potential for therapuetic applications in tissue replacement therapy. Reprogramming somatic cells from a patient donor to generate pluripotent stem cells involves both ethical concerns inherent in the use of embryonic and oocyte-derived stem cells, as well as issues of histocompatibility. Among the various pluripotent stem cells, induced pluripotent stem cells (iPSC)--derived by ectopic expression of four reprogramming factors in donor somatic cells--are superior in terms of ethical use, histocompatibility, and derivation method. However, iPSC also show genetic and epigenetic differences that limit their differentiation potential, functionality, safety, and potential clinical utility. Here, we discuss the unique characteristics of iPSC and approaches that are being taken to overcome these limitations. PMID:22819821
Tobin, Stacey C; Kim, Kitai
Stem cell–based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.
Lindvall, Olle; Kokaia, Zaal
Liver transplantation is currently the only therapeutic option for patients with end-stage chronic liver disease and for severe acute liver failure. Because of limited donor availability, attention has been focused on the possibility to restore liver mass and function through cell transplantation. Stem cells are a promising source for liver repopulation after cell transplantation, but whether or not the adult mammalian liver contains hepatic stem cells is highly controversial. Part of the problem is that proliferation of mature adult hepatocytes is sufficient to regenerate the liver after two-thirds partial hepatectomy or acute toxic liver injury and participation of stem cells is not required. However, under conditions in which hepatocyte proliferation is blocked, undifferentiated epithelial cells in the periportal areas, called “oval cells”, proliferate, differentiate into hepatocytes and restore liver mass. These cells are referred to as facultative liver stem cells, but they do not repopulate the normal liver after their transplantation. In contrast, epithelial cells isolated from the early fetal liver can effectively repopulate the normal liver, but they are already traversing the hepatic lineage and may not be true stem cells. Mesenchymal stem cells and embryonic stem cells can be induced to differentiate along the hepatic lineage in culture, but at present these cells are inefficient in repopulating the liver. This review will characterize these various cell types and compare the properties of these cells and the conditions under which they do or do not repopulate the liver following their transplantation.
Oertel, Michael; Shafritz, David A.
During tissue development and regeneration, stem cells respond to the entire milieu of their environment, through dynamic interactions with the surrounding cells, extracellular matrix, and cascades of molecular and physical regulatory factors. A new generation of culture systems is emerging to offer some of the biological fidelity of a whole organism within highly controllable in vitro settings and provide the cultured cells with the combinations of factors they normally encounter in vivo. There is a growing notion that such "biomimetic" systems are essential for unlocking the full potential of stem cells - for tissue regeneration as well as biological research. In this chapter, we discuss the biological principles for designing biologically inspired culture systems for stem cell research and focus on the control of stem cell microenvironment through surface patterning, microfluidics, and electrical stimulation.
Freytes, Donald O.; Vunjak-Novakovic, Gordana
Stem cells are characterized by the ability to remain undifferentiated and to self-renew. Embryonic stem cells derived from blastocysts are pluripotent (able to differentiate into many cell types). Adult stem cells, which were traditionally thought to be monopotent multipotent, or tissue restricted, have recently also been shown to have pluripotent properties. Adult bone marrow stem cells have been shown to
Carl T. Henningson; Marisha A. Stanislaus; Alan M. Gewirtz
Many elderly people worldwide lose the neurosensory part of their ear and turn deaf. Cochlear implants to restore some hearing\\u000a after neurosensory hearing loss are, at present, the only therapy for these people. In contrast to this therapy, replacement\\u000a of hair cells via stem cell therapies holds the promise for a cure. We review here current insights into embryonic, adult,
Kirk Beisel; Laura Hansen; Garrett Soukup; Bernd Fritzsch
The lung is composed of two major anatomically distinct regions—the conducting airways and gas-exchanging airspaces. From a cell biology standpoint, the conducting airways can be further divided into two major compartments, the tracheobronchial and bronchiolar airways, while the alveolar regions of the lung make up the gas-exchanging airspaces. Each of these regions consists of distinct epithelial cell types with unique cellular physiologies and stem cell compartments. This chapter focuses on model systems with which to study stem cells in the adult tracheobronchial airways, also referred to as the proximal airway of the lung. Important in such models is an appreciation for the diversity of stem cell niches in the conducting airways that provide localized environmental signals to both maintain and mobilize stem cells in the setting of airway injury and normal cellular turnover. Because cellular turnover in airways is relatively slow, methods for analysis of stem cells in vivo have required prior injury to the lung. In contrast, ex vivo and in vitro models for analysis of airway stem cells have used genetic markers to track lineage relationships together with reconstitution systems that mimic airway biology. Over the past decades, several widely acceptable methods have been developed and used in the characterization of adult airway stem/ progenitor cells. These include localization of label-retaining cells (LRCs), retroviral tagging of epithelial cells seeded into xenografts, air–liquid interface cultures to track clonal proliferative potential, and multiple transgenic mouse models. This chapter reviews the biologic context and use of these models while providing detailed methods for several of the more broadly useful models for studying adult airway stem/progenitor cell types.
Liu, Xiaoming; Driskell, Ryan R.; Engelhardt, John F.
Brain tumors display striking heterogeneity of cellular morphology and differentiation status. Recent studies have identified\\u000a tumor subpopulations in several brain tumor types that self-renew and can propagate tumor formation in mice models. These\\u000a cells, called tumor stem cells, are defined functionally but several markers are under investigation to identify brain tumor\\u000a stem cells. Although no marker has proven absolutely informative
Jeremy N. Rich
Human embryonic stem cells (HESC) can potentially generate every body cell type, making them excellent candidates for cell- and tissue-replacement therapies. HESC are typically cultured with animal-derived 'serum replacements' on mouse feeder layers. Both of these are sources of the nonhuman sialic acid Neu5Gc, against which many humans have circulating antibodies. Both HESC and derived embryoid bodies metabolically incorporate substantial
Maria J Martin; Alysson Muotri; Fred Gage; Ajit Varki
A mini-documentary discussing the remarkable regenerative capabilities of the planarian, and how HHMI researcher Alejandro Snchez Alvarado uses them to study the biology of stem cells. This presentation is also featured on the DVD Potent Biology: Stem Cells, Cloning, and Regeneration, available for free from HHMI. This video is 11 minutes and 46 seconds in length, and available for download in Quicktime (114 MB) and Windows Media (156 MB) formats. All Stem Cell videos are located at: http://www.hhmi.org/biointeractive/stemcells/video.html.
Alejandro SĂÂˇnchez Alvarado (Howard Hughes Medical Institute;)
Direct-to-consumer (DTC) advertising of suspect goods and services has burgeoned because of the Internet. Despite very limited approval for use, DTC stem cell-marketed "treatments" have emerged for an array of conditions, creating global public health and safety risks. However, it remains unclear whether such use of stem cells is subject to drugs or biologics regulations. To address this gap, regulatory agencies should be given clear authority, and the international community should create a framework for appropriate stem cell use. In addition, consumer protection laws should be used to scrutinize providers. PMID:22972840
Liang, Bryan A; Mackey, Tim K
Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, leading to relapse. This highlights the importance and urgency of developing approaches to target MM stem cells. However, very little is known about the molecular characteristics of the MM stem cells, which makes it difficult to target MM stem cells therapeutically. Evidence of the existence of a myeloma stem cell has been provided by Matsui et al. showing that the CD138- and CD20+ fraction, which is a minor population of the MM cells, has a greater clonogenic potential and has the phenotype of a memory B-cell (CD19+, CD27+). In this review, we report recent progress of cell surface markers in cancer stem cells, especially in myeloma and the molecular mechanisms related to drug resistance and myeloma disease progression.
Cruz, Richard Dela; Tricot, Guido; Zangari, Maurizio; Zhan, Fenghuang
Hematopoietic stem cells (HSC) continuously replenish the blood and immune systems. Their activity must be sustained throughout\\u000a life to support optimal immune responses. It has been thought that stem cells may be somewhat protected from age because of\\u000a their perpetual requirement to replenish the blood, however studies over the past 10 years have revealed dramatic changes\\u000a in HSC function and phenotype
S. M. Chambers; M. A. Goodell
\\u000a Embryonic and adult stem cells are considered to be potential sources of insulin-secreting cells to be transplanted into type\\u000a 1 and advanced stages of type 2 diabetic patients. After years of study, the key determinants necessary for the differentiation\\u000a process are beginning to be fully characterised, and several protocols have been published. However, investigators still have\\u000a to face several problems
Enrique Roche; Nestor Vicente-Salar; Maribel Arribas; Beatriz Paredes
The concept that stem cells can be used to replace and regenerate tissue was founded over half a century ago using hematopoietic stem cells in the clinical field of bone marrow transplantation. The development of human embryonic stem cell lines and patient-specific induced pluripotent stem cells has the potential to overcome the problem presented by shortages of immunologically compatible hematopoietic stem cell donors. This review summarizes the current advances made and limitations to be overcome in order to realize the full potential of engineering blood from pluripotent stem cells for clinical use. PMID:21232565
Dravid, Gautam G; Crooks, Gay M
The renal disease is a common problem in human society. End-stage renal disease is a big heath problem in the United States and in all places of the world. Embryonic stem cells, pluripotent derivatives of the inner cell mass of the blastocyst, are the most primitive cell type likely to find application in cell therapy. Their potential to generate any
Hongbao Ma; Shen Cherng; Yan Yang
Stem cells in the kidney. The kidney is derived from the ureteric bud and the metanephrogenic mesenchyme, and these two progenitor cells differentiate into more than 26 different cell types in the adult kidney. The ureteric bud contains the precursor of the epithelial cells of the collecting duct and the renal mesenchyme contains precursors of all the epithelia of the
Qais Al-Awqati; Juan A. Oliver
\\u000a Significant advances have been made in stem cell research over the past decade. A number of non-hematopoietic sources of stem\\u000a cells (or progenitor cells) have been identified including endothelial stem cells and neural stem cells. These discoveries\\u000a have been a major step towards the potential regeneration of organs for clinical applications using stem cells. The worldwide\\u000a shortage of donor kidneys
Takashi Yokoo; Akira Fukui; Kei Matsumoto; Tetsuya Kawamura
hen groups of stem cell researchers meet or when stem cell researchers publish their data and interpre- tations in scientific journals, a small cluster of important issues loom over the discussions yet often go unremarked. These issues influence much of the nature, direction, and funding of stem cell investigations, particularly those in- volving adult stem cells. The unmentionable issues are
NEIL D. THEISE
There has been increasing interest in the application of mesenchymal stem cells (MSCs) in regenerative medicine in recent years. In this context, the beneficial effects of MSCs have been ascribed mainly to a paracrine action rather than to direct replacement of the injured tissue. Indeed, MSCs produce a great variety of trophic and immunomodulatory factors. In this chapter, we provide an overview of growth factors and chemokines involved in stimulation of cell proliferation, inhibition of apoptosis, enhancement of angiogenesis, and suppression of inflammatory and immune response. In addition, we discuss the emerging role of the extracellular vesicles released from MSCs as possible paracrine mediators. PMID:22968371
Bruno, Stefania; Collino, Federica; Tetta, Ciro; Camussi, Giovanni
Following high-dose chemotherapy for the treatment of malignant disease, reinfusion of peripheral blood stem cells collected during treatment with growth factors usually results in delayed platelet engrafiment as compared to neutrophil recovery. The overa...
Background: Many cancers appear to arise from rare, primitive self-renewing cancer cells, that are biologically distinct from their more numerous differentiated progeny characterizing the malignancy. Although the clinical significance of these cancer stem...
The stem cell field in veterinary medicine continues to evolve rapidly both experimentally and clinically. Stem cells are most commonly used in clinical veterinary medicine in therapeutic applications for the treatment of musculoskeletal injuries in horses and dogs. New technologies of assisted reproduction are being developed to apply the properties of spermatogonial stem cells to preserve endangered animal species. The same methods can be used to generate transgenic animals for production of pharmaceuticals or for use as biomedical models. Small and large animal species serve as valuable models for preclinical evaluation of stem cell applications in human beings and in veterinary patients in areas such as spinal cord injury and myocardial infarction. However, these applications have not been implemented in the clinical treatment of veterinary patients. Reviews on the use of animal models for stem cell research have been published recently. Therefore, in this review, animal model research will be reviewed only in the context of supporting the current clinical application of stem cells in veterinary medicine. PMID:21371354
Fortier, Lisa A; Travis, Alexander J
The discovery of induced pluripotent stem (iPS) cells has broadened the promises of regenerative medicine through the generation of syngeneic replacement cells or tissues via the differentiation of patient-specific iPS cells. To apply iPS cell-mediated therapy to patients with genetic disorders, however, genome-editing technologies with high efficiency and specificity are needed. Recently, several targeted genome-editing strategies mediated by zinc finger nuclease and transcription activator-like effector nuclease have been applied to human and mouse iPS cells. Furthermore, spontaneous homologous recombination can restore genotype to wild type in mouse iPS cells heterozygous for genetic mutations. Through genome editing, the clinical application of patient-specific genetic mutation-free iPS cells to genetic disorders can finally be realized. PMID:22487259
Cheng, Li-Tao; Sun, Liang-Tso; Tada, Takashi
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
I. V. Viktorov
Embryonic stem cells are undifferentiated pluripotent cells that can indefinitely grow in vitro. They are derived from the inner mass of early embryos. Because of their ability to differentiate into all three embryonic germ layers, and finally into specialized somatic cell types, human embryonic stem cells represent important material for studying developmental biology and cell replacement therapy. They are usually
Ger P. A. Bongaerts; René S. V. M. Severijnen
An essential aspect of stem cell culture is the successful maintenance of the undifferentiated state. Many types of stem cells are FGF2 dependent, and pluripotent stem cells are maintained by replacing FGF2-containing media daily, while tissue-specific stem cells are typically fed every 3rd day. Frequent feeding, however, results in significant variation in growth factor levels due to FGF2 instability, which limits effective maintenance due to spontaneous differentiation. We report that stabilization of FGF2 levels using controlled release PLGA microspheres improves expression of stem cell markers, increases stem cell numbers and decreases spontaneous differentiation. The controlled release FGF2 additive reduces the frequency of media changes needed to maintain stem cell cultures, so that human embryonic stem cells and induced pluripotent stem cells can be maintained successfully with biweekly feedings. PMID:23437109
Lotz, Steven; Goderie, Susan; Tokas, Nicolas; Hirsch, Sarah E; Ahmad, Faizzan; Corneo, Barbara; Le, Sheila; Banerjee, Akhilesh; Kane, Ravi S; Stern, Jeffrey H; Temple, Sally; Fasano, Christopher A
Based on findings that cancer cell clonogens exhibit stem cell features, it has been suggested that cancer stem-like cells are relatively radioresistant owing to different intrinsic and extrinsic factors, including quiescence, activated radiation response mechanisms (e.g., enhanced DNA repair, upregulated cell cycle control mechanisms and increased free-radical scavengers) and a surrounding microenvironment that enhances cell survival mechanisms (e.g., hypoxia and interaction with stromal elements). However, these radiosensitivity features are probably dynamic in nature and come into play at different times during the course of chemo/radiotherapy. Therefore, different molecularly targeted radiosensitization strategies may be needed at different stages of therapy. This article describes potential sensitization approaches based on the dynamics and changing properties of cancer stem-like cells during therapy. PMID:21062156
Hittelman, Walter N; Liao, Yong; Wang, Li; Milas, Luka
Based on findings that cancer cell clonogens exhibit stem cell features, it has been suggested that cancer stem-like cells are relatively radioresistant owing to different intrinsic and extrinsic factors, including quiescence, activated radiation response mechanisms (e.g., enhanced DNA repair, upregulated cell cycle control mechanisms and increased free-radical scavengers) and a surrounding microenvironment that enhances cell survival mechanisms (e.g., hypoxia and interaction with stromal elements). However, these radiosensitivity features are probably dynamic in nature and come into play at different times during the course of chemo/radiotherapy. Therefore, different molecularly targeted radiosensitization strategies may be needed at different stages of therapy. This article describes potential sensitization approaches based on the dynamics and changing properties of cancer stem-like cells during therapy.
Hittelman, Walter N; Liao, Yong; Wang, Li; Milas, Luka
Technologies to isolate colonies of human pluripotent stem cells from other cell types in a high-throughput manner are lacking. A microfluidic-based approach that exploits differences in the adhesion strength between these cells and a substrate may soon fill the gap.
Abilez, Oscar J.; Wu, Joseph C.
Significant attention is currently directed to the biological and therapeutic capabilities of stem cells for developing novel treatments for acute and chronic kidney diseases. To date, viable sources of stem cells for renal therapies include adult bone marrow and embryonic tissues, including the metanephric mesenchyme and mesonephros. Native adult kidney stem cells have yet to be identified. Systemically introduced stem
Daniel J. Mollura; Joshua M. Hare; Hamid Rabb
Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a 'nursing' role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance - they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy. PMID:22771454
Seiler, Magdalene J; Aramant, Robert B
Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a ‘nursing’ role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance – they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy.
Seiler, Magdalene J.; Aramant, Robert B.
Stem cells, including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells and amniotic fluid stem cells have the potential to be expanded and differentiated into various cell types in the body. Efficient differentiation of stem cells with the desired tissue-specific function is critical for stem cell-based cell therapy, tissue engineering, drug discovery and disease modeling. Bioreactors provide a great platform to regulate the stem cell microenvironment, known as “niches”, to impact stem cell fate decision. The niche factors include the regulatory factors such as oxygen, extracellular matrix (synthetic and decellularized), paracrine/autocrine signaling and physical forces (i.e., mechanical force, electrical force and flow shear). The use of novel bioreactors with precise control and recapitulation of niche factors through modulating reactor operation parameters can enable efficient stem cell expansion and differentiation. Recently, the development of microfluidic devices and microbioreactors also provides powerful tools to manipulate the stem cell microenvironment by adjusting flow rate and cytokine gradients. In general, bioreactor engineering can be used to better modulate stem cell niches critical for stem cell expansion, differentiation and applications as novel cell-based biomedicines. This paper reviews important factors that can be more precisely controlled in bioreactors and their effects on stem cell engineering.
Liu, Meimei; Liu, Ning; Zang, Ru; Li, Yan; Yang, Shang-Tian
Replacement of diseased tissues with healthy cells derived from embryonic stem (ES) cells has a potential to become, in the future, a better alternative to current treatments of a number of conditions characterized by irreversible tissue injury, such as heart and liver failure, diabetes mellitus and neurodegeneration. However, several obstacles have to be overcome before this new therapeutic modality becomes
Lukas P. Frenzel; Jürgen Hescheler
The purpose of this essay is to stimulate academic discussion about the ethical justification of using human primordial stem cells for tissue transplantation, cell replacement, and gene therapy. There are intriguing alternatives to using embryos obtained from elective abortions and in vitro fertilisation to reconstitute damaged or dysfunctional human organs. These include the expansion and transplantation of latent adult progenitor
John R Meyer
Huntington's disease (HD) is a late-onset neurodegenerative disease characterized by a progressive loss of medium spiny neurons in the basal ganglia. The development of stem cell-based therapies for HD aims to replace lost neurons and/or to prevent cell death. This review will discuss pre-clinical studies which have utilized stem or progenitor cells for transplantation therapy using HD animal models. In several studies, neural stem and progenitor cells used as allotransplants and xenografts have been shown to be capable of surviving transplantation and differentiating into mature GABAergic neurons, resulting in behavioral improvements. Beneficial effects have also been reported for transplantation of stem cells derived from non-neural tissue, for example, mesenchymal- and adipose-derived stem cells, which have mainly been attributed to their secretion of growth and neurotrophic factors. Finally, we review studies using stem cells genetically engineered to over-express defined neurotrophic factors. While these studies prove the potential of stem cells for transplantation therapy in HD, it also becomes clear that technical and ethical issues regarding the availability of stem cells must be solved before human trials can be conducted. PMID:23097329
Maucksch, Christof; Vazey, Elena M; Gordon, Renee J; Connor, Bronwen
Pluripotent stem cells are able to self-renew and to differentiate into all adult cell types. Many studies report data describing these cells and characterize them in molecular terms. Gene expression data of pluripotent and non-pluripotent cells from mouse were assembled. Machine learning was applied to classify samples into pluripotent and non-pluripotent cells. To identify minimal sets of best biomarkers, three methods were used: information gain, random forests, and genetic algorithm. PMID:22874386
Schmidt, Rainer; Scheubert, Lena; Lustrek, Mitja; Repsilber, Dirk; Fuellen, Georg
One of the defining features of the liver is the capacity to maintain a constant size despite injury. Although the precise molecular signals involved in the maintenance of liver size are not completely known, it is clear that the liver delicately balances regeneration with overgrowth. Mammals, for example, can survive surgical removal of up to 75% of the total liver mass. Within 1 week after liver resection, the total number of liver cells is restored. Moreover, liver overgrowth can be induced by a variety of signals, including hepatocyte growth factor or peroxisome proliferators; the liver quickly returns to its normal size when the proliferative signal is removed. The extent to which liver stem cells mediate liver regeneration has been hotly debated. One of the primary reasons for this controversy is the use of multiple definitions for the hepatic stem cell. Definitions for the liver stem cell include the following: (1) cells responsible for normal tissue turnover, (2) cells that give rise to regeneration after partial hepatectomy, (3) cells responsible for progenitor-dependent regeneration, (4) cells that produce hepatocyte and bile duct epithelial phenotypes in vitro, and (5) transplantable liver-repopulating cells. This review will consider liver stem cells in the context of each definition.
DUNCAN, ANDREW W.; DORRELL, CRAIG; GROMPE, MARKUS
Recovery of lost brain function is an important issue in medical studies because neurons of the central nervous system (CNS) have poor potential for regeneration. Since few CNS diseases can be treated completely by medicines, regenerative therapy by using stem cells should be studied as a new type of therapeutic intervention. The efficacy of cell replacement therapy in Parkinson's disease has been well investigated. Several studies on fetal tissue transplantation have revealed that quantity and purity of transplanted cells are necessary for recovery of symptoms. SFEB (Serum-free floating culture of embryoid body-like aggregates) method is capable of inducing multi-potential CNS progenitors that can be steered to differentiate into region-specific tissues. On the basis of the existing knowledge of embryology, we have succeeded in the generating of various types of neurons such as telencephalic, cerebeller (Purkinje and granule cells), retinal (photoreceptor cells) and hypothalamic neurons. Application of this culture method to human ES (hES) cells is necessary for clinical purpose: however, poor survival of hES cells in SFEB culture might limit the possibility of using these cells for future medical applications. We found that a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, markedly diminished the dissociation-induced apoptosis of hES cells and enabled the cells to form aggregates in SFEB culture. For both mouse and human ES cells, SFEB culture is a favorable method that can generate large amounts of region-specific neurons. However, stem cell-based therapy continues to face several obstacles. It is important that researchers in the basic sciences and clinical medicine should discuss these problems together to overcome both scientific and ethical issues related to stem cells. PMID:18975604
Wataya, Takafumi; Muguruma, Keiko; Sasai, Yoshiki
The ability to reprogram virtually any cell of human origin to behave like embryonic or pluripotent stem cells is a major breakthrough in stem cell biology. Human induced pluripotent stem cells (iPSC) provide a unique opportunity to study "disease in a dish" within a defined genetic and environmental background. Patient-derived iPSCs have been successfully used to model cardiomyopathies, rhythm disorders and vascular disorders. They also provide an exciting opportunity for drug discovery and drug repurposing for disorders with a known molecular basis including childhood onset heart disease, particularly cardiac genetic disorders. The review will discuss their use in drug discovery, efficacy and toxicity studies with emphasis on challenges in pediatric-focused drug discovery. Issues that will need to be addressed in the coming years include development of maturation protocols for iPSC-derived cardiac lineages, use of iPSCs to study not just cardiac but extra-cardiac phenotypes in the same patient, scaling up of stem cell platforms for high-throughput drug screens, translating drug testing results to clinical applications in the paradigm of personalized medicine, and improving both the efficiency and the safety of iPSC-derived lineages for future stem cell therapies. PMID:23292032
Patel, Pranali; Mital, Seema
Different types of stem cell maintain the skin's epidermis and contribute to its healing after damage. The identity of a stem-cell type that gives rise to different epidermal-cell lineages has just been revealed.
Stem cells possess the potential to cure a myriad of ailments ranging from congenital diseases to illnesses acquired through the physiological process of aging. In the adult, these cells are extremely rare and often difficult to isolate in numbers sufficient to apply to medical treatment. Ex vivo expansion of these cells will be required for most meaningful interventions. The discovery of stem/progenitor cell inversion offers a new avenue for obtaining sufficient numbers of stem cells. Adult progenitor cells are much more common than quiescent stem cells and can be isolated with minimal interventions; therefore, inversion of progenitors to stem cells may become a feasible approach for therapeutic purposes. Stem cells are known to possess few mitochondria, and mitochondrial biogenesis is required for stem cell differentiation. The microtubule cytoskeleton is a major regulator for mitochondrial biogenesis. Investigations in the area of controlling cell differentiation and inducing phenotypic inversion, possibly through manipulation of mitochondrial biogenesis, may contribute to stem cell-based therapies.
Siggins, Robert W.; Zhang, Ping; Welsh, David; LeCapitaine, Nicole J.; Nelson, Steve
The goal of tissue engineering is to create a functional replacement for tissues damaged by injury or disease. In many cases, impaired tissues cannot provide viable cells, leading to the investigation of stem cells as a possible alternative. Cartilage, in particular, may benefit from the use of stem cells since the tissue has low cellularity and cannot effectively repair itself. To address this need, researchers are investigating the chondrogenic capabilities of several multipotent stem cell sources, including adult and extra-embryonic mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Comparative studies indicate that each cell type has advantages and disadvantages, and while direct comparisons are difficult to make, published data suggest some sources may be more promising for cartilage regeneration than others. In this review, we identify current approaches for isolating and chondrogenically differentiating MSCs from bone marrow, fat, synovium, muscle, and peripheral blood, as well as cells from extra-embyronic tissues, ESCs, and iPSCs. Additionally, we assess chondrogenic induction with growth factors, identifying standard cocktails used for each stem cell type. Cell-only (pellet) and scaffold-based studies are also included, as is a discussion of in vivo results.
Beane, Olivia S.; Darling, Eric M.
The review gives the present views on the origin, identification markers, and specific features of the phenotype of glioma stem cells, considers how the latter interact with the cells of the microenvironment in the perivascular niches. Many signaling pathways that determine properties, such a higher invasive and angiogenic ability, a marked metabolic shift toward glycolysis, and resistance to radio- and chemotherapy, are shown to be activated in the glioma stem cells. The exposure of the latter may contribute to the improvement of the results of treatment for malignant gliomas. PMID:24006765
Borisov, K E; Sakaeva, D D
Stem cell niches provide a regulatory microenvironment that retains stem cells and promotes self-renewal. Recently in Developmental Cell, Rinkevich et al. (2013) showed that cell islands (CIs) of Botryllus schlosseri, a colonial chordate, provide niches for maintaining cycling stem cells that migrate from degenerated CIs to newly formed buds. PMID:23369706
Zhou, Yi; Lewallen, Michelle; Xie, Ting
Cell lines and genetically modified single cell organisms have been considered patentable subjects for the last two decades. However, despite the technical patentability of genes and stem cell lines, social and legal controversy concerning their 'ownership' has surrounded stem cell research in recent years. Some granted patents on stem cells with extremely broad claims are casting a shadow over the
Enca Martin-Rendon; Derek J. Blake
The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters
Tito Fojo; Susan Bates; Michael Dean
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. PMID:23294307
Lairson, Luke L; Lyssiotis, Costas A; Zhu, Shoutian; Schultz, Peter G
The historical, lexical and conceptual issues embedded in stem cell biology are reviewed from technical, ethical, philosophical, judicial, clinical, economic and biopolitical perspectives. The mechanisms assigning the simultaneous capacity to self-renew and to differentiate to stem cells (immortal template DNA and asymmetric division) are evaluated in the light of the niche hypothesis for the stemness state. The induction of cell pluripotency and the different stem cells sources are presented (embryonic, adult and cord blood). We highlight the embryonic and adult stem cell properties and possible therapies while we emphasize the particular scientific and social values of cord blood donation to set up cord blood banks. The current scientific and legal frameworks of cord blood banks are reviewed at an international level as well as allogenic, dedicated and autologous donations. The expectations and the challenges in relation to present-day targeted diseases like diabetes mellitus type I, Parkinson's disease and myocardial infarction are evaluated in the light of the cellular therapies for regenerative medicine. PMID:23283430
Monti, Manuela; Perotti, Cesare; Del Fante, Claudia; Cervio, Marila; Redi, Carlo Alberto
The mouse prostate has been the primary focus of research in regards to both normal stem cells and cancer stem cell-like cell\\u000a populations in the animal prostate. The proximal region is the probable location of stem cells because it contains a high\\u000a number of label-retaining cells, which express stem-cell specific markers, that are resistant to androgen ablation and have\\u000a a
Alexander Yu. Nikitin; Melia G. Nafus; Zongxiang Zhou; Chun-Peng Liao; Pradip Roy-Burman
\\u000a Embryonic stem cells, or induced pluripotent cells derived from somatic cells, can yield differentiated progeny with potential\\u000a applicability for tissue repair. This chapter describes the generation of embryonic stem cells from gamete-derived uniparental\\u000a embryos. These embryonic stem cells can be patient-derived and potentially histocompatible with the gamete donor. The production\\u000a of uniparental embryos followed by derivation of embryonic stem cells
Sigrid Eckardt; K. John McLaughlin
Stem cell transplantation represents a critical approach for the treatment of many malignant and non- malignant diseases. The foundation for these approaches is the ability to cryopreserve marrow cells for future use. This technique is routinely employed in all autologous settings and is critical for cord blood transplantation. A variety of cryopreservatives have been used with multiple freezing and thawing
David Berz; Elise M. McCormack; Eric S. Winer; Gerald A. Colvin; Peter J. Quesenberry
In the adult kidney, different populations of progenitor cells (or stem cells) have been identified. These cells may represent a remnant of embryonic stem cells in the adult tissue, or populations of bone-marrow-derived stem cells homed within the kidney and modified by the local microenvironment. This modification may be the expression of a partial commitment or of different degrees of maturation. Resident stem cells may account for the growth of the organ during development, for the physiological cell turnover, and for the repair of kidney damage. In addition, stem cells derived from the bone marrow and migrated through the circulation to the site of the damage may contribute to tissue repair. Preliminary studies suggest that this regenerative potential of stem cells could be exploited for therapeutic purposes by administration of ex vivo expanded stem cell populations or by development of strategies aimed to expand and differentiate local stem cells. PMID:18350496
Bussolati, B; Camussi, G
\\u000a Cell biologists have long realized that most cells do not live as long as the organisms they comprise; thus, cells in almost\\u000a every tissue need to be renewed\\/replaced during the natural lifespan of the organism. Depending on the turnover rate of cells\\u000a in any given organ, this process can be very frequent or very rare. Epithelial cells in the mouth
Research on human embryonic stem cells (hESCs) and induced pluripotent (iPS) stem cells is currently a field of great potential in biomedicine. These cells represent a highly valuable tool for developmental biology studies, disease models, and drug screening and toxicity. The ultimate goal of hESCs and iPS cell research is the treatment of diseases or disorders for which there is currently no treatment or existing therapies are only partially effective. Despite the disproportionate short-term hopes generated, which are putting too much pressure on scientists, the international scientific community is making rapid progress in understanding hESCs and iPS cells. Nonetheless, great efforts have to be made to provide an answer to still quite basic questions concerning their biology. Moreover, translation to clinical applications in cell replacement therapy requires prior solution to ethical barriers. The recent development of iPS cells has provided a strong alternative to overcome ethical issues concerning hESCs. However, an in-depth characterization of their genetic and epigenetic features, as well as their differentiation potential still remains to be undertaken. This chapter will describe, precisely, what the critical issues are, where scientific and ethical barriers stand, and how we are to overcome them. Only then, we shall finally discover whether hESCs and iPS cells will allow building reproducible disease models, and whether they really are a safe tool, with great potential for regenerative medicine. PMID:22457113
Martín, Miguel; Menéndez, Pablo
Three types of stem cells, embryonic, adult and induced pluripotent stem cells, are currently studied by scientists. Obama's presidency has opened the door for stem cell research by revoking statements and orders made during the former President Bush's administration. This provisional period will allow the National Institute of Health to rewrite policies governing how federal funds are distributed for stem cell research. These new regulations will grant more freedom to researchers wishing to use stem cells in their research and challenge them to determine the most appropriate stem cell treatment for a given disorder.
Bellayr, IH; Li, Y
Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.
Shinozuka, Kazutaka; Dailey, Travis; Tajiri, Naoki; Ishikawa, Hiroto; Kaneko, Yuji; Borlongan, Cesar V.
The present invention is directed to methods for readily propagating somatic liver stem cells. The methods comprise enhancing guanine nucleotide (GNP) biosynthesis, thereby expanding guanine nucleotide pools. This in turn conditionally suppresses asymmetric cell kinetics in the explanted cells. The methods of the invention include pharmacological methods and genetic methods. For example, the resulting cultured somatic liver stem cells can be used for a variety of applications including cell replacement therapies, gene therapies, drug discovery applications, and tissue engineering applications, such as the generation of artificial liver.
Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair.\\u000a Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and\\u000a a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in
Gillian Farnie; Robert B. Clarke
Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide\\u000a a dynamic tool for revealing early embryonic development, modeling pathological processes, and developing therapeutics through\\u000a drug discovery and potential cell replacement. The first step toward the utilities of human PSCs is directed differentiation\\u000a to functionally specialized cell\\/tissue types. Following developmental principles, human ESCs,
Huisheng Liu; Su-Chun Zhang
Background: A number of cardiovascular, neurological, musculoskeletal and other diseases have a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue engineering. Experimental data and the first clinical trials employing stem cells have shown their broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems. Aims: Here, we briefly review the main achievements and trends in cell-based therapy, with an emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells. Discussion: Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC seems to be safe and might be considered to be a leading candidate for human application to treat pathologies that affect the cardiovascular, neurological and musculoskeletal systems.
Sykova, Eva; Forostyak, Serhiy
Germline stem (GS) cells can only differentiate into germline cells, while multipotent germ stem (mGS) cells, like embryonic stem (ES) cells, can differentiate into various somatic cells and tissues. The proteomic profiles in GS and mGS cells were compared by two-dimensional gel electrophoresis. Ten down-regulated and 16 up-regulated proteins were differentially expressed in mGS cells in comparison to GS cells,
Hajime Kurosaki; Yasuhiro Kazuki; Masaharu Hiratsuka; Toshiaki Inoue; Yasuhisa Matsui; Chi Chiu Wang; Mito Kanatsu-Shinohara; Takashi Shinohara; Tosifusa Toda; Mitsuo Oshimura
Adult stem cells reside in specialized microenvironments, or niches, that have an important role in regulating stem cell behaviour. Therefore, tight control of niche number, size and function is necessary to ensure the proper balance between stem cells and progenitor cells available for tissue homeostasis and wound repair. The stem cell niche in the Drosophila male gonad is located at
Justin Voog; Cecilia D'Alterio; D. Leanne Jones
Stem cell research and related therapies (including regenerative medicine and cellular therapies) could have a significant near-term impact on worldwide public health and aging. One reason is the industry's strong linkage between policy, science, industry, and patient advocacy, as was clear in the attendance and programming at the 7(th) annual World Stem Cell Summit held in Pasadena, California, October 3-5, 2011. A special conference session sponsored by the SENS Foundation discussed how stem cell therapies are being used to extend healthy life span. Stem cells are useful not only in cell-replacement therapies, but also in disease modeling, drug discovery, and drug toxicity screening. Stem cell therapies are currently being applied to over 50 diseases, including heart, lung, neurodegenerative, and eye disease, cancer, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Dozens of companies are developing therapeutic solutions that are in different stages of clinical use and clinical trials. Some high-profile therapies include Dendreon's Provenge for prostate cancer, Geron's first-ever embryonic stem cell trials for spinal cord injury, Fibrocell's laViv cellular therapy for wrinkles, and well-established commercial skin substitutes (Organogenesis' Apligraf and Advanced BioHealing's Dermagraft). Stem cell policy issues under consideration include medical tourism, standards for large-scale stem cell manufacturing, and lingering ethical debates over the use of embryonic stem cells. Contemporary stem cell science advances include a focus on techniques for the direct reprogramming of cells from one lineage to another without returning to pluripotency as an intermediary step, improved means of generating and characterizing induced pluripotent cells, and progress in approaches to neurodegenerative disease. PMID:22175514
Stem cell transplantation is currently generating a significant interest for use in the future treatment of cardiovascular\\u000a diseases. Stem cell populations are rapidly increasing, and we are still in the search of optimal cell types to use in clinical\\u000a trials as bone marrow stem cells did not show significant improvement in cardiac function following transplantation. Experimental\\u000a stem cell studies raised
Dinender K. Singla
\\u000a Basic and clinical research on adult stem cells is progressing rapidly. New technology that can generate iPS (induced pluripotent\\u000a stem cells) cells from various types of tissue may completely change the stem cell world and regenerative medicine. In terms\\u000a of clinical applications, both bone marrow and skin are very attractive sources of adult stem cells because they are highly\\u000a accessible
A signature characteristic of stem cells is their ability to self-renew, affording a theoretically limitless ability to produce daughter cells and their descendents. This near-timeless dimension of stem cell function is not free of the constraints of place. The idea that highly specialized 'microenvironmental' cues participate in the regulation of stem cells has evidence in classic embryology and more recently
Gregor B Adams; David T Scadden
Stem cells are of considerable importance in prostate cancer because of the theory that cancer cells represent the malignant counterparts of normal tissue stem cells. We have shown that murine prostatic stem cells reside in the proximal region of the pros...
S. N. Salm
Auditory neurons, the target neurons of the cochlear implant, degenerate following a sensorineural hearing loss. The goal of this research is to direct the differentiation of embryonic stem cells (SCs) into bipolar auditory neurons that can be used to replace degenerating neurons in the deafened mammalian cochlea. Successful replacement of auditory neurons is likely to result in improved clinical outcomes
B. Coleman; J. B. Fallon; L. N. Pettingill; M. G. de Silva; R. K. Shepherd
While scientific community disagrees about similarities and differences between human embryonic stem (hES) cells and human\\u000a induced pluripotent stem (hiPS) cells, some politicians embrace translational hiPS cell research as a replacement for translational\\u000a hES cell research. We examine the ethical relevance of the main differences between hES and hiPS cell-based therapies and\\u000a discuss whether, given the current state of knowledge,
Kristina Hug; Göran Hermerén
While scientific community disagrees about similarities and differences between human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells, some politicians embrace translational hiPS cell research as a replacement for translational hES cell research. We examine the ethical relevance of the main differences between hES and hiPS cell-based therapies and discuss whether, given the current state of knowledge, certain differences are essential. We discuss whether well-founded preferences can be made in hypothetical scenarios with varying levels of patient safety, treatment efficacy, treatment accessibility and ethical controversy. PMID:21461713
Hug, Kristina; Hermerén, Göran
According to the cancer stem cell hypothesis tumors are maintained by a cancer stem cell population which is able to initiate and maintain tumors. Tumor-initiating stem cells display stem or progenitor cell properties such as self-renewal and capacity to re-establish tumors that recapitulate the tumor of origin. In this paper, we discuss data relative to the presence of cancer stem cells in human renal carcinoma and their possible origin from normal resident stem cells. The cancer stem cells identified in human renal carcinomas are not derived from the normal CD133+ progenitors of the kidney, but rather from a more undifferentiated population that retains a mesenchymal phenotype. This population is able to self-renewal, clonogenicity, and in vivo tumor initiation. Moreover, they retain pluripotent differentiation capability, as they can generate not only the epithelial component of the tumor, but also tumor endothelial cells. This suggests that renal cancer stem cells may contribute to the intratumor vasculogenesis.
Bussolati, Benedetta; Brossa, Alessia; Camussi, Giovanni
Stem cell therapy holds great promises in medical treatment by, e.g., replacing lost cells, re-constitute healthy cell populations and also in the use of stem cells as vehicles for factor and gene delivery. Embryonic stem cells have rightfully attracted a large interest due to their proven capacity of differentiating into any cell type in the embryo in vivo. Tissue-specific stem
Ana I Teixeira; Joshua K Duckworth; Ola Hermanson
Cell replacement therapy using stem cell transplantation holds much promise in the field of regenerative medicine. In the area of hematopoietic stem cell transplantation, O6- methylguanine-DNA methyltransferase MGMT (P140K) gene-mediated drug resistance-based in vivo enrichment strategy of donor stem cells has been shown to achieve up to 75%-100% donor cell engraftment in the host's hema- topoietic stem cell compartment following
Antonio S. J. Lee; Prathibha Kahatapitiya; Belinda Kramer; Josephine E. Joya; Jeff Hook; Renjing Liu; Galina Schevzov; Ian E. Alexander; Geoff McCowage; Didier Montarras; Peter W. Gunning; EDNA C. HARDEMANb
There is a growing interest in medical potential of stem cells which may be used someday to create new tissue. Suggested applications involve a board spectrum ranging from the replacement for cells destroyed by diseases to even organ transplants. As ethical and legal controversy makes uncertain the future of embryonic stem cells research, attention has been recently turned to adult stem cells to discover whether they also can serve to transplantation. In this article we present data indicating that adult stem cells found in areas of the body like blood, skin, lymph and nervous systems, may be more versatile than previously assumed and in certain conditions can broke tissue barriers for differentiation. Thus, in this respect they can behave like their own pluripotent ancestors, although underlying mechanisms for this phenomena are still not clear. Furthermore, the following issues are shortly discussed: What are the characteristics of the different stem cells and where they can be found. What are experimental evidences that stem cells can be used for brain repair. What are the main problems must be solved before their clinical application and the risk-benefit assessment. The possible strategies and targets for stem cell therapies of neurological diseases. PMID:12189682
\\u000a The lung epithelium is structurally and functionally a complex tissue composed of different cell types. It is exposed to toxic\\u000a agents and pathogens that can with time result in various lung diseases, including lung cancer. The major cell types in the\\u000a proximal tracheobronchial part are basal cells, goblet cells, ciliated cells, and cells of the submucosal glands. Further\\u000a down the
Magnus Karl Magnusson; Olafur Baldursson; Thorarinn Gudjonsson
In light of the latest developments in the field of molecular hematology, we herein discuss the reported cases that have presented dyskeratosis congenita as one of the inherited stem cell diseases causing limbal stem cell deficiency.
Deniz Aslan; Rustu Fikret Akata
Mammary tumor formation is thought to be the consequence of transformation of undifferentiated pluripotent stem cells. Little is known about the character of mammary gland stem cells. Examination of mammary gland development has indicated that there may b...
S. C. Heffelfinger
The purpose of this grant project was to identify and characterize methods for ablation of chronic myelogenous leukemia (CML) stem cells. Numerous studies have shown that malignant stem cells lie at the heart of CML disease. Therefore, specific targeting ...
C. T. Jordan
The present invention relates to compositions and methods concerning isolated gastrointestinal stem cells. Particularly, the invention provides isolated gastrointestinal stem cells comprising a CD45 negative marker, a collagen IV negative marker, and that...
S. J. Henning
There is increasing evidence that breast cancers are driven by a small subcomponent that displays stem cell properties. We hypothesize that these breast cancer stem cells are resistant to chemotherapy and may contribute to tumor relapse. In order to provi...
M. S. Wicha
In this study, we characterized the self-renewal capability, multi-lineage differentiation capacity, and clonogenic efficiency of human dental pulp stem cells (DPSCs). DPSCs were capable of forming ectopic dentin and associated pulp tissue in vivo. Stromal-like cells were reestablished in culture from primary DPSC transplants and re-transplanted into immunocompromised mice to generate a dentin-pulp-like tissue, demonstrating their self-renewal capability. DPSCs were
S. Gronthos; J. Brahim; W. Li; L. W. Fisher; N. Cherman; A. Boyde; P. DenBesten; P. Gehron Robey; S. Shi
Stem cells have been isolated from human embryos, fetal tissue, umbilical cord blood (UCB), and also from "adult" sources. Adult stem cells are found in many tissues of the body and are capable of maintaining, generating, and replacing terminally differentiated cells. A source of pluripotent stem cells has been recently identified in UCB that can also differentiate across tissue lineage boundaries into neural, cardiac, epithelial, hepatocytic, and dermal tissue. Thus, UCB may provide a future source of stem cells for tissue repair and regeneration. Its widespread availability makes UCB an attractive source for tissue regeneration. UCB-derived stem cells offer multiple advantages over adult stem cells, including their immaturity, which may play a significant role in reduced rejection after transplantation into a mismatched host and their ability to produce larger quantities of homogenous tissue or cells. While research with embryonic stem cells continues to generate considerable controversy, human umbilical stem cells provide an alternative cell source that has been more ethically acceptable and appears to have widespread public support. This review will summarize the in vitro and in vivo studies examining UCB stem cells and their potential use for therapeutic application for nonhematopoietic tissue and cell regeneration. PMID:17949892
van de Ven, Carmella; Collins, Daniel; Bradley, M Brigid; Morris, Erin; Cairo, Mitchell S
Establishment of human embryonic stem cell lines is one the major achievements in the biological science in the XX century and has excited a wide scientific and social response as embryonic stem cells can be regarded in future as unlimited source of transplantation materials for the replacement cell therapy. To date human embryonic cell lines are obtained in more than 20 countries. In our country the embryonic stem cell researches are carried out in the Institute of Cytology RAS and the Institute of Gene Biology RAS. ESC lines are derived from placed in culture inner cell mass of human preimplantation blastocysts used in the in vitro fertilization procedure. Studies with human ESC go in several directions. Much attention is paid to the elaboration of the optimal conditions for ESC cultivation, mainly to the development of cultivation methods excluding animal feeder cells and other components of animal origin. Another direction is a scale analysis of gene expression specific for the embryonic state of the cells and corresponding signaling pathways. Many efforts are concentrated to find conditions for the directed differentiation of ESC into different tissue-specific cells. It has been shown that ESC are able to differentiate in vitro practically into any somatic cells. Some works are initiated to develop methods for the "therapeutic cloning", that is transfer and reactivation of somatic nuclei into enucleated oocytes or embryonic stem cell cytoblasts. Of great importance is human ESC line standardization. However, the standard requirements for the cells projected for research or therapeutic purposes may be different. It has been found that many permanent human ESC lines undergo genetic and epigenetic changes and, therefore, the cell line genetic stability should be periodically verified. The main aim of the review presented is a detailed consideration of the works analyzing the genetic stability of human and mouse ESC lines. Human ESC lines established in our and as well as in other countries couldn't be used so far in clinical practice. It is highly probable that undifferentiated ESC cannot be applied for therapeutic purposes because of the risk of their malignant transformation. Therefore, main efforts should be focused on the production of progenitor and highly differentiated cells suitable for transplantation derived from ESC. PMID:17918336
Nikol'ski?, N N; Giba?, I A; Somova, N V
The skin epidermis and its array of appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury. Different resident skin stem cell pools contribute to the maintenance and repair of the
Cédric Blanpain; Elaine Fuchs
Stem cell transplantation (SCT) has emerged to be an appealing tool for repair medicine. In the treatment of ischemic heart diseases, SCT will be of great help because it is capable of replacing scar with new myocardial tissue. Among the many candidate cell lines for SCT, embryonic stem cells (ESCs) have their unique advantages. However, the controversy about the host
Xin Yuan; Hao Zhang; Ying-jie Wei; Sheng-shou Hu
The synergism of stem cell biology and biomaterial technology promises to have a profound impact on stem-cell-based clinical applications for tissue regeneration. Biomaterials development is rapidly advancing to display properties that, in a precise and physiological fashion, could drive stem-cell fate both in vitro and in vivo. Thus, the design of novel materials is trying to recapitulate the molecular events involved in the production, clearance and interaction of molecules within tissue in pathologic conditions and regeneration of tissue/organs. In this review we will report on the challenges behind translating stem cell biology and biomaterial innovations into novel clinical therapeutic applications for tissue and organ replacements (graphical abstract). PMID:21740963
Martino, Sabata; D'Angelo, Francesco; Armentano, Ilaria; Kenny, Josč Maria; Orlacchio, Aldo
Cardiovascular disease is the leading cause of death in developed countries and is one of the leading causes of disease burden in developing countries. Therapies have markedly increased survival in several categories of patients, nonetheless mortality still remains high. For this reason high hopes are associated with recent developments in stem cell biology and regenerative medicine that promise to replace
F. Gandolfi; A. Vanelli; G. Pennarossa; M. Rahaman; F. Acocella; T. A. L. Brevini
The proliferation of stem cell research, conflated with its ethical and moral implications, has led governments to attempt regulation of both the science and funding of stem cells. Due to a diversity of opinions and cultural viewpoints, no single policy or set of rules exist to govern stem cell research. Instead, each country has developed its own policy. The following map catalogs the general legal and political milleu regarding stem cell research by country.
Dhar, Deepali; Hsi-en Ho, John
\\u000a Mammalian spermatogenesis endures on the persistent activity of stem cells, i.e., their self-renewal and production of differentiating\\u000a progeny. The normal functioning of stem cells explicitly requires a particular microenvironment within the tissue – the stem cell niche – as an indispensable element. While the mammalian spermatogenic stem cell niche system remains to be fully elucidated, recent\\u000a knowledge has improved our
The mathematical models prevalently used to represent stem cell proliferation do not have the level of accuracy that might\\u000a be desired. The hyperbolastic growth models promise a greater degree of precision in representing data of stem cell proliferation.\\u000a The hyperbolastic growth model H3 is applied to experimental data in both embryonic stem cells and adult mesenchymal stem\\u000a cells. In the
Mohammad A. Tabatabai; Zoran Bursac; Wayne M. Eby; Karan P. Singh
A new theory about the development of solid tumours is emerging from the idea that solid tumours, like normal adult tissues,\\u000a contain stem cells (called cancer stem cells) and arise from them. Genetic mutations encoding for proteins involved in critical\\u000a signalling pathways for stem cells such as BMP, Notch, Hedgehog and Wnt would allow stem cells to undergo uncontrolled proliferation
Victoria Bolós; Moisés Blanco; Vanessa Medina; Guadalupe Aparicio; Silvia Díaz-Prado; Enrique Grande
Recent progress in the field of the stem cell research has given new hopes to treat and even cure diverse degenerative disorders\\u000a and incurable diseases in human. Particularly, the identification of a rare population of adult stem cells in the most tissues\\/organs\\u000a in human has emerged as an attractive source of multipotent stem\\/progenitor cells for cell replacement-based therapies and\\u000a tissue
Murielle Mimeault; Surinder K. Batra
This paper reports on a research project which examined media coverage and audience perceptions of stem cells and stem cell research in Hungary, using focus groups and a media analysis. A background study was also conducted on the Hungarian legal, social and political situation linked to stem cell research, treatment and storage. Our data show how stem cell research\\/treatments were
Lilla Vicsek; Júlia Gergely
|In this study, we examined 96 undergraduate non-science majors' conceptions of stem cells, stem cell research, and cloning. This study was performed at a large, Midwest, research extensive university. Participants in the study were asked to answer 23 questions relating to stem cells, stem cell research, and cloning in an on-line assessment before…
Concannon, James P.; Siegel, Marcelle A.; Halverson, Kristy; Freyermuth, Sharyn
Stem cell therapy in curing dangerous diseases usually is main target of many researches about stem cells. In the world, researching and applying stem cells to cure diseases got some great achievements while there is a few in Viet Nam. In recently years, Laboratory of Stem cell R&D, University of Science, VNU HCM city carried out some researches about pre-
Phan Kim Ngoc; Pham Van Phuc; Viet Nam
In this study, we examined 96 undergraduate non-science majors' conceptions of stem cells, stem cell research, and cloning. This study was performed at a large, Midwest, research extensive university. Participants in the study were asked to answer 23 questions relating to stem cells, stem cell research, and cloning in an on-line assessment before and after instruction. Two goals of the
James P. Concannon; Marcelle A. Siegel; Kristy Halverson; Sharyn Freyermuth
Myeloproliferative disorders (MPDs), typified by robust marrow and extramedullary hematopoiesis, have a propensity to progress to acute leukemia. Although the hematopoietic stem cell (HSC) origin of MPDs was suggested over 30 years ago, only recently the HSC-specific effects of MPD molecular mutations have been investigated. The pivotal role of BCR-ABL in chronic myeloid leukemia (CML) development provided the rationale for
C H M Jamieson; C F Barroga; W P Vainchenker; CHM Jamieson
Although little has been written about iatrogenic limbal stem cell deficiency, patients with this disorder are probably more common than the literature might suggest. It is important to recognize this disorder as a limbal deficiency, since standard medical therapies will not address its etiology. The sequelae of this condition include stromal scarring and significant loss of vision. Fortunately, phacoemulsification has
Gary S. Schwartz; Edward J. Holland
Stem cells play an essential role in embryonic development, cell differentiation and tissue regeneration. Tissue homeostasis in adults is maintained by adult stem cells resident in the niches of different tissues. As one kind of adult stem cell, epidermal stem cells have the potential to generate diversified types of progeny cells in the skin. Although its biology is still largely unclarified, epidermal stem cells are widely used in stem cell research and regenerative medicine given its easy accessibility and pluripotency. Despite the same genome, cells within an organism have different fates due to the epigenetic regulation of gene expression. In this review, we will briefly discuss the current understanding of epigenetic modulation in epidermal stem cells. PMID:23999591
Shen, Qi; Jin, Hongchuan; Wang, Xian
Stem cells play an essential role in embryonic development, cell differentiation and tissue regeneration. Tissue homeostasis in adults is maintained by adult stem cells resident in the niches of different tissues. As one kind of adult stem cell, epidermal stem cells have the potential to generate diversified types of progeny cells in the skin. Although its biology is still largely unclarified, epidermal stem cells are widely used in stem cell research and regenerative medicine given its easy accessibility and pluripotency. Despite the same genome, cells within an organism have different fates due to the epigenetic regulation of gene expression. In this review, we will briefly discuss the current understanding of epigenetic modulation in epidermal stem cells.
Shen, Qi; Jin, Hongchuan; Wang, Xian
Technology for converting human cells to pluripotent stem cell using induction processes has the potential to revolutionize regenerative medicine. However, the production of these so called iPS cells is still quite inefficient and may be dominated by stochastic effects. In this work we build mass-action models of the core regulatory elements controlling stem cell induction and maintenance. The models include not only the network of transcription factors NANOG, OCT4, SOX2, but also important epigenetic regulatory features of DNA methylation and histone modification. We show that the network topology reported in the literature is consistent with the observed experimental behavior of bistability and inducibility. Based on simulations of stem cell generation protocols, and in particular focusing on changes in epigenetic cellular states, we show that cooperative and independent reaction mechanisms have experimentally identifiable differences in the dynamics of reprogramming, and we analyze such differences and their biological basis. It had been argued that stochastic and elite models of stem cell generation represent distinct fundamental mechanisms. Work presented here suggests an alternative possibility that they represent differences in the amount of information we have about the distribution of cellular states before and during reprogramming protocols. We show further that unpredictability and variation in reprogramming decreases as the cell progresses along the induction process, and that identifiable groups of cells with elite-seeming behavior can come about by a stochastic process. Finally we show how different mechanisms and kinetic properties impact the prospects of improving the efficiency of iPS cell generation protocols.
Gracio, Filipe; Cabral, Joaquim; Tidor, Bruce
Technology for converting human cells to pluripotent stem cell using induction processes has the potential to revolutionize regenerative medicine. However, the production of these so called iPS cells is still quite inefficient and may be dominated by stochastic effects. In this work we build mass-action models of the core regulatory elements controlling stem cell induction and maintenance. The models include not only the network of transcription factors NANOG, OCT4, SOX2, but also important epigenetic regulatory features of DNA methylation and histone modification. We show that the network topology reported in the literature is consistent with the observed experimental behavior of bistability and inducibility. Based on simulations of stem cell generation protocols, and in particular focusing on changes in epigenetic cellular states, we show that cooperative and independent reaction mechanisms have experimentally identifiable differences in the dynamics of reprogramming, and we analyze such differences and their biological basis. It had been argued that stochastic and elite models of stem cell generation represent distinct fundamental mechanisms. Work presented here suggests an alternative possibility that they represent differences in the amount of information we have about the distribution of cellular states before and during reprogramming protocols. We show further that unpredictability and variation in reprogramming decreases as the cell progresses along the induction process, and that identifiable groups of cells with elite-seeming behavior can come about by a stochastic process. Finally we show how different mechanisms and kinetic properties impact the prospects of improving the efficiency of iPS cell generation protocols. PMID:23667423
Grácio, Filipe; Cabral, Joaquim; Tidor, Bruce
Stems improve the mechanical stability of tibial components in total knee replacement (TKR), but come at a cost of stress shielding along their length. Their advantages include resistance to shear, reduced tibial lift-off and increased stability by reducing micromotion. Longer stems may have disadvantages including stress shielding along the length of the stem with associated reduction in bone density and a theoretical risk of subsidence and loosening, peri-prosthetic fracture and end-of-stem pain. These features make long stems unattractive in the primary TKR setting, but often desirable in revision surgery with bone loss and instability. In the revision scenario, stems are beneficial in order to convey structural stability to the construct and protect the reconstruction of bony defects. Cemented and uncemented long stemmed implants have different roles depending on the nature of the bone loss involved. This review discusses the biomechanics of the design of tibial components and stems to inform the selection of the component and the technique of implantation. PMID:22844039
Scott, C E H; Biant, L C
Three types of stem cells, embryonic, adult, and induced pluripotent stem cells, are currently studied by scientists. Barack Obama's presidency has opened the door for stem cell research by revoking statements and orders made during the former President Bush's administration. This provisional period will allow the National Institute of Health to rewrite policies governing how federal funds are distributed for
Ian H. Bellayr; Yong Li
Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Using MS-based metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is
Oscar Yanes; Julie Clark; Diana M Wong; Gary J Patti; Antonio Sánchez-Ruiz; H Paul Benton; Sunia A Trauger; Caroline Desponts; Sheng Ding; Gary Siuzdak
Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state,
Isabel P Neuringer; Scott H Randell
The proliferative compartment of stratified squamous epithelia consists of stem and transient amplifying (TA) keratinocytes. Some polypeptides are more abundant in putative epidermal stem cells than in TA cells, but no polypeptide confined to the stem cells has yet been identified. Here we show that the p63 transcription factor, a p53 homologue essential for regenerative proliferation in epithelial development, distinguishes
Graziella Pellegrini; Elena Dellambra; Osvaldo Golisano; Enrica Martinelli; Ivana Fantozzi; Sergio Bondanza; Diego Ponzin; Frank McKeon; Michele de Luca
It is well established that tissue repair depends on stem cells and that chronic wounds predispose to tumour formation. However, the association between stem cells, wound healing and cancer is poorly understood. Lineage tracing has now shown how stem cells are mobilized to repair skin wounds and how they contribute to skin tumour development. The signalling pathways, including WNT and
Esther N. Arwert; Esther Hoste; Fiona M. Watt
Summary The evidence for mammary epithelial stem cells and their phenotypic characteristics in normal and neoplastic development is reviewed. The presence of stem cells in all parts of the mammary parenchyma at all stages of differentiation has been demonstrated by transplantation experiments. The phenotypic characterization of stem cells has been defined by a battery of monospecific antibodies. These studies suggest
D. Medina; G. H. Smith
The objectives of this review were first to critically review what is known about the effects of aging on stem cells in general, and hematopoietic stem cells in particular. Secondly, evidence is marshaled in support of the hypothesis that aging stem cells play a critical role in determining the effects of aging on organ function, and ultimately on the lifespan
Gary Van Zant; Ying Liang
|The goal of this lesson is to present the basic scientific knowledge about stem cells, the promise of stem cell research to medicine, and the ethical considerations and arguments involved. One of the challenges of discussing stem cell research is that the field is constantly evolving and the most current information changes almost daily. Few…
Miller, Roxanne Grietz
Peripheral blood stem cells are rapidly becoming a major source of hemopoietic stem cells for transplanta- tion in patients with various hematological and oncolog- ical conditions. Clinical results of peripheral blood stem cell transplantation (PBSCT) have shown benefits of earlier hemopoietic recovery, lower morbidity, and greater cost-effectiveness compared with conventional bone marrow transplant. Moreover, the relative ease of obtaining large
ALBERT K. W. LIE; L. BIK TO
This is a chronicle of concepts in the field of epidermal stem cell biology and a historic look at their development over time. The past 25 years have seen the evolution of epidermal stem cell science, from first fundamental studies to a sophisticated science. The study of epithelial stem cell biology was aided by the ability to visualize the distribution
Although biochemical signals that modulate stem cell self-renewal and differentiation were extensively studied, only recently were the mechanical properties of a stem cell's microenvironment shown to regulate its behavior. It would be desirable to have independent control over biochemical and mechanical cues, to analyze their relative and combined effects on stem-cell function. We developed a synthetic, interfacial hydrogel culture system,
Krishanu Saha; Albert J. Keung; Elizabeth F. Irwin; Yang Li; Lauren Little; David V. Schaffer; Kevin E. Healy
Purpose of review The capacity of the liver to regenerate and maintain a constant size despite injury is unique. However, the exact mechanisms are not completely clear. Cell transplantation has been proposed as an alternative treatment of liver diseases. Recent progress has been reported on the generation of stem/progenitor cells that may differentiate towards the hepatic lineage. However, it is currently difficult to determine which of the stem/progenitor cell populations are the best for therapy of a given disease. Recent findings The limited access to donor human hepatocytes has opened a great interest on the generation of hepatocyte-like cells. Several potential cell sources have been identified. However, general standardization of the methods to evaluate these cells is particularly important for the promise of stem/progenitor-derived hepatocyte-based therapies. Moreover, innovations aimed at improving hepatocyte delivery, survival and engraftment have recently opened the field of organ engineering that may improve the perspective of liver repopulation. Summary Here we review current evidence reported from the perspective of potential clinical applications of different hepatic cell sources with repopulation capacities and the future perspectives and tools that can facilitate the translation of laboratory work into clinical success.
Soto-Gutierrez, Alejandro; Navarro-Alvarez, Nalu; Yagi, Hiroshi; Yarmush, Martin L.
Emerging evidence suggests the existence of a tumorigenic population of cancer cells that demonstrate stem cell-like properties such as self-renewal and multipotency. These cells, termed cancer stem cells (CSC), are able to both initiate and maintain tumor formation and progression. Studies have shown that CSC are resistant to traditional chemotherapy treatments preventing complete eradication of the tumor cell population. Following treatment, CSC are able to re-initiate tumor growth leading to patient relapse. Salivary gland cancers are relatively rare but constitute a highly significant public health issue due to the lack of effective treatments. In particular, patients with mucoepidermoid carcinoma or adenoid cystic carcinoma, the two most common salivary malignancies, have low long-term survival rates due to the lack of response to current therapies. Considering the role of CSC in resistance to therapy in other tumor types, it is possible that this unique sub-population of cells is involved in resistance of salivary gland tumors to treatment. Characterization of CSC can lead to better understanding of the pathobiology of salivary gland malignancies as well as to the development of more effective therapies. Here, we make a brief overview of the state-of-the-science in salivary gland cancer, and discuss possible implications of the cancer stem cell hypothesis to the treatment of salivary gland malignancies. PMID:23810400
Adams, April; Warner, Kristy; Nör, Jacques E
Carcinogenesis and tumor cells had long been thought to be produced by genetic mutations, until the emergence of the cancer stem cell (CSC) model. This relatively new model reveals another layer of complexity in malignancy formation and maintenance. However, these hard-to-track subpopulations have not only been challenging to understand at the molecular level but have also prevented the development of novel CSC-based cancer therapies. Accumulating evidence from previous studies has suggested that CSCs might be derived from either somatic stem cells (SCCs) or differentiated progenitor cells and that they constantly reestablish their niches; these factors underlie the variability in their frequencies and biological marker expression. Therefore, we present the hypothesis that CSCs possess constantly evolving features. During tumorigenesis, the characteristics of the CSCs may change, thus presenting a "moving target". We also suggest that a multifaceted, integrated strategy combining traditional cell surface markers and transcriptional factor targeting methods to identify "stemness" should lead to the better isolation and characterization of CSCs. Corresponding laboratory approaches to test this hypothesis are also provided. PMID:23484674
Hu, Yijun; Yu, Xiya; Liu, Shupeng; Liu, Shanrong
Neural stem cells are potentially a source of cells not only for replacement therapy but also as drug vectors, bringing bioactive molecules into the brain. Stem cell-like cells can be isolated readily from the human brain, thus, it is important to find culture systems that enable expansion in a multipotent state to generate cells that are of potential use for therapy. Currently, two systems have been described for the maintenance and expansion of multipotent progenitors, an adhesive substrate bound and the neurosphere culture. Both systems have pros and cons, but the neurosphere may be able to simulate the three-dimensional environment of the niche in which the cells reside in vivo. Thus, the neurosphere, when used and cultured appropriately, can expand and provide important information about the mechanisms that potentially control neural stem cells in vivo. PMID:19089354
Giachino, Claudio; Basak, Onur; Taylor, Verdon
The nervous system is characterized by its complex network of highly specialized cells that enable us to perceive stimuli from the outside world and react accordingly. The computational integration enabled by these networks remains to be elucidated, but appropriate sensory input, processing, and motor control are certainly essential for survival. Consequently, loss of nervous tissue due to injury or disease represents a considerable biomedical challenge.Stem cell research offers the promise to provide cells for nervous system repair to replace lost and damaged neural tissue and alleviate disease. We provide a protocol-based chapter on fundamental principles and procedures of pluripotent stem cell (PSC) differentiation and neural transplantation. Rather than detailed methodological step-by-step descriptions of these procedures, we provide an overview and highlight the most critical aspects and key steps of PSC neural induction, subtype specification in different in vitro systems, as well as neural cell transplantation to the central nervous system. We conclude with a summary of suitable readout methods including in vitro phenotypic analysis, histology, and functional analysis in vivo. PMID:24029933
Döbrössy, Máté; Pruszak, Jan
Stem cells exert therapeutic effects against ischemic stroke via transplantation of exogenous stem cells or stimulation of endogenous stem cells within the neurogenic niches of subventricular zone and subgranular zone, or recruited from the bone marrow through peripheral circulation. In this paper, we review the different sources of stem cells that have been tested in animal models of stroke. In addition, we discuss specific mechanisms of action, in particular neurovascular repair by endothelial progenitor cells, as key translational research for advancing the clinical applications of stem cells for ischemic stroke.
Shinozuka, Kazutaka; Dailey, Travis; Tajiri, Naoki; Ishikawa, Hiroto; Kim, Dae Won; Pabon, Mibel; Acosta, Sandra; Kaneko, Yuji; Borlongan, Cesar V
Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed
Nicolas Christoforou; Behzad N. Oskouei; Paul Esteso; Christine M. Hill; Jeffrey M. Zimmet; Weining Bian; Nenad Bursac; Kam W. Leong; Joshua M. Hare; John D. Gearhart; Arnold Schwartz
Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic\\u000a disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified\\u000a cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some\\u000a of the seminal
David W. Emery; Tamon Nishino; Ken Murata; Michalis Fragkos; George Stamatoyannopoulos
\\u000a Since the early days of cardiovascular biology, it has been believed that mammalian adult cardiomyocytes exit from the cell\\u000a cycle soon after birth, with the total number of cardiomyocytes being pre-determined. Recently, the identification of resident\\u000a cardiac stem\\/progenitor cells by several independent laboratories has challenged this long-held paradigm and has provoked\\u000a an exponential increase in the number of investigations. As
Ronglih Liao; Regina L. Sohn
Subpopulations of cancer cells with stem cell-like characteristics, termed cancer stem cells, have been identified in a wide range of human cancers. Cancer stem cells are defined by their ability to self-renew as well as recapitulate the original heterogeneity of cancer cells in culture and in serial xenotransplants. Not only are cancer stem cells highly tumorigenic, but these cells are implicated in tumor resistance to conventional chemotherapy and radiotherapy, thus highlighting their significance as therapeutic targets. Considerable similarities have been found between cancer stem cells and normal stem cells on their dependence on certain signaling pathways. More specifically, the core stem cell signaling pathways, such as the Wnt, Notch and Hedgehog pathways, also critically regulate the self-renewal and survival of cancer stem cells. While the oncogenic functions of Notch pathway have been well documented, its role in cancer stem cells is just emerging. In this chapter, we will discuss recent advances in cancer stem cell research and highlight the therapeutic potential of targeting Notch in cancer stem cells. PMID:22399347
Wang, Jialiang; Sullenger, Bruce A; Rich, Jeremy N
Many organs respond to physiological challenges by changing tissue size or composition. Such changes may originate from tissue-specific stem cells and their supportive environment (niche). The endocrine system is a major effector and conveyor of physiological changes and as such could alter stem cell behavior in various ways. In this review, we examine how hormones affect stem cell biology in four different organs: the ovary, intestine, hematopoietic system, and mammary gland. Hormones control every stage of stem cell life, including establishment, expansion, maintenance, and differentiation. The effects can be cell autonomous or non-cell autonomous through the niche. Moreover, a single hormone can affect different stem cells in different ways or affect the same stem cell differently at various developmental times. The vast complexity and diversity of stem cell responses to hormonal cues allow hormones to coordinate the body's reaction to physiological challenges. PMID:23875645
Gancz, Dana; Gilboa, Lilach
Skeletal muscle is a highly specialized tissue composed of non-dividing, multi-nucleated muscle fibres that contract to generate force in a controlled and directed manner. Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells, which generate both differentiated muscle fibres and specialized muscle-forming stem cells known as satellite cells. Satellite cells remain associated with muscle fibres after birth and are responsible for muscle growth and repair throughout life. Failure in satellite cell function can lead to delayed, impaired or failed recovery after muscle injury, and such failures become increasingly prominent in cases of progressive muscle disease and in old age. Recent progress in the isolation of muscle satellite cells and elucidation of the cellular and molecular mediators controlling their activity indicate that these cells represent promising therapeutic targets. Such satellite cell-based therapies may involve either direct cell replacement or development of drugs that enhance endogenous muscle repair mechanisms. Here, we discuss recent breakthroughs in understanding both the cell intrinsic and extrinsic regulators that determine the formation and function of muscle satellite cells, as well as promising paths forward to realizing their full therapeutic potential. PMID:21727135
Shadrach, Jennifer L; Wagers, Amy J
Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy-based model in which cancer stem cells (CSCs) have the ability both to self-renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications. PMID:23180591
Sugihara, Eiji; Saya, Hideyuki
Large-scale proliferation and multi-lineage differentiation capabilities make neural stem cells (NSCs) a promising renewable source of cells for therapeutic applications. However, the practical application for neuronal cell replacement is limited by heterogeneity of NSC progeny, relatively low yield of neurons, predominance of astrocytes, poor survival of donor cells following transplantation and the potential for uncontrolled proliferation of precursor cells. To address these impediments, we have developed a method for the generation of highly enriched immature neurons from murine NSC progeny. Adaptation of the standard differentiation procedure in concert with flow cytometry selection, using scattered light and positive fluorescent light selection based on cell surface antibody binding, provided a near pure (97%) immature neuron population. Using the purified neurons, we screened a panel of growth factors and found that bone morphogenetic protein-4 (BMP-4) demonstrated a strong survival effect on the cells in vitro, and enhanced their functional maturity. This effect was maintained following transplantation into the adult mouse striatum where we observed a 2-fold increase in the survival of the implanted cells and a 3-fold increase in NeuN expression. Additionally, based on the neural-colony forming cell assay (N-CFCA), we noted a 64 fold reduction of the bona fide NSC frequency in neuronal cell population and that implanted donor cells showed no signs of excessive or uncontrolled proliferation. The ability to provide defined neural cell populations from renewable sources such as NSC may find application for cell replacement therapies in the central nervous system.
Azari, Hassan; Osborne, Geoffrey W.; Yasuda, Takahiro; Golmohammadi, Mohammad G.; Rahman, Maryam; Deleyrolle, Loic P.; Esfandiari, Ebrahim; Adams, David J.; Scheffler, Bjorn; Steindler, Dennis A.; Reynolds, Brent A.
Many adult stem cells divide asymmetrically to balance self-renewal and differentiation, thereby maintaining tissue homeostasis. Asymmetric stem cell divisions depend on asymmetric cell architecture (i.e., cell polarity) within the cell and/or the cellular environment. In particular, as residents of the tissues they sustain, stem cells are inevitably placed in the context of the tissue architecture. Indeed, many stem cells are polarized within their microenvironment, or the stem cell niche, and their asymmetric division relies on their relationship with the microenvironment. Here, we review asymmetric stem cell divisions in the context of the stem cell niche with a focus on Drosophila germ line stem cells, where the nature of niche-dependent asymmetric stem cell division is well characterized.
Yamashita, Yukiko M.; Yuan, Hebao; Cheng, Jun; Hunt, Alan J.
Multiple sclerosis is an autoimmune disease that destroys myelin-forming oligodendrocytes of the CNS. While the damage can\\u000a be partially controlled using anti-inflammatory cytokines and steroids, endogenous repair is insufficient to replace lost\\u000a cells. Until now cell replenishment (transplant therapy) has been viewed as unlikely to succeed due to allograft rejection\\u000a in this sensitized immune environment. However, advances in stem cell
Cui P. Chen; Mary E. Kiel; Dorota Sadowski; Randall D. McKinnon
Stem cells, while difficult to define, hold great promise as tools for understanding development and as therapy. However, this difficulty in defining stem cells has led to a multiplicity of stem cells that may or may not be distinct. The lack of common standards or definitions, the absence of a common forum for discussion, and the range in the ability to manipulate his/her favorite system of stem cells has led to further fragmentation of a field bedeviled by controversy. I suggest that stratification and classification of stem cells on the basis of their function, characteristics, and capabilities would be of enormous benefit to the community. This absence of uniform nomenclature and classification has led to many contradictory claims as to the abilities of stem cells and has made it very difficult to generalize across systems and cell types. I illustrate the problem by providing two examples of how the lack of uniform definitions has slowed progress. I suggest that the effort to establish a consensus on what constitutes a tissue-specific stem cell (definition) and how one would stratify cells (classification) would greatly facilitate progress and perhaps help resolve some of the outstanding controversies. PMID:15588501
Rao, Mahendra S
The use of stem cells is considered a promising therapy for tissue regeneration and repair, particularly for tissues injured\\u000a through degeneration, ischemia and inflammation. Bone marrow (BM)-derived haematopoietic stem cells (HSCs) are rare populations\\u000a of multipotent stem cells that have been identified as promising potential candidates for treating a broad range of conditions.\\u000a Although research into the use of stem
Dean Philip John Kavanagh; Neena Kalia
Stem cells are one of the most fascinating areas of biology today. Stem cells have two important characteristics that distin - guish them from other types of cells. First, they are unspecialized cells that renew themselves for long periods through cell division.The second is that under certain physiologic or experimental conditions, they can be induced to become cells with special
Fazlur Rahman; Bikash Subedi; Sirajul Haque; Sajal Krishna Banerjee; Chaudhury MeshkatAhmed; Khairul Anam; Khurshed Ahmed; A. Rashid
Stem cells possess the ability of self-renewal and differentiation into specific cell types. Therefore, stem cells have great potentials in fundamental biology studies and clinical applications. The most urgent desire for stem cell research is to generate appropriate artificial stem cell culture system, which can mimic the dynamic complexity and precise regulation of the in vivo biochemical and biomechanical signals, to regulate and direct stem cell behaviors. Precise control and regulation of the biochemical and biomechanical stimuli to stem cells have been successfully achieved using emerging micro/nanoengineering techniques. This review provides insights into how these micro/nanoengineering approaches, particularly microcontact printing and elastomeric micropost array, are applied to create dynamic and complex environment for stem cells culture. PMID:22639443
Sun, Yubing; Weng, Shinuo; Fu, Jianping
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The use of stem cells to improve recovery of the injured heart after myocardial infarction (MI) is an important emerging therapeutic strategy. However, recent reviews of clinical trials of stem cell therapy for MI and ischemic heart disease recovery report that less than half of the trials found only small improvements in cardiac function. In clinical trials, bone marrow, peripheral blood, or umbilical cord blood cells were used as the source of stem cells delivered by intracoronary infusion. Some trials administered only a stem cell mobilizing agent that recruits endogenous sources of stem cells. Important challenges to improve the effectiveness of stem cell therapy for CVD include: (1) improved identification, recruitment, and expansion of autologous stem cells; (2) identification of mobilizing and homing agents that increase recruitment; and (3) development of strategies to improve stem cell survival and engraftment of both endogenous and exogenous sources of stem cells. This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.
Hoover-Plow, Jane; Gong, Yanqing
This case explores the political and ethical issues associated with stem cell research. Students read the case describing Christopher Reeve’s accident and injuries and his advocacy for stem cell research along with background readings on stem cells and the ethics of stem cell research. They are then assigned to one of four stakeholder groups and asked to develop a position on whether or not the U.S. Senate should expand stem cell research with a focus on the ethics underlying the issue. They present their positions in class in a simulated public hearing.
Post, Doug M.; Knutson, Doug
Although the use of stem cells in cell-replacement therapies by transplantation is obvious, another equally important and interesting application of stem cells is to use them in disease modeling. Disease models serve as a platform to dissect the biochemical mechanisms of normal phenotypes and the processes which go awry during disease conditions. Particularly in complex, multigenic diseases, molecular studies lead to a greater understanding of the disease, and perhaps more targeted approaches for therapies. Stem cells provide an ideal in vitro system in which to study events related to development at the molecular and cellular level. Neural stem cells have been used as excellent models to study the mechanisms of differentiation of cells of the central nervous system. These studies may be particularly relevant to diseases of complex etiology such as psychiatric illnesses, neurodegenerative diseases and brain tumors. Stem cell-derived systems are also being developed to create models of cardiovascular disease. The application of stem cells to the study of cardiovascular illnesses, and vertebrate heart development, is discussed. PMID:18220912
Ruiz-Lozano, Pilar; Rajan, Prithi
Trophoblast stem (TS) cells are ideal models to investigate trophectoderm differentiation and placental development. Herein, we describe the derivation of rabbit trophoblast stem cells from embryonic stem (ES) cells. Rabbit ES cells generated in our laboratory were induced to differentiate in the presence of BMP4 and TS-like cell colonies were isolated and expanded. These cells expressed the molecular markers of
Tao Tan; Xianghui Tang; Jing Zhang; Yuyu Niu; Hongwei Chen; Bin Li; Qiang Wei; Weizhi Ji; Anton Wutz
Objective: Immune-related mechanisms are involved in various neurological diseases and although mesenchymal stem cells (MSCs) have been shown to repair and replace injured neurons, it remains uncertain what the immune cells in the brain do during this process. Microglial cells are the representatives of immune cells in the brain. Microglial cells, injured neurons and stem cells often coexist in the
Xiaoguang Luo; Chunlin Ge; Yan Ren; Jin Zhou; Xiaolei Li; Rong Yan; Chaodong Zhang
Summary Mesenchymal stem cells (MSCs) have the potential to replace or restore the function of damaged tissues and offer much promise in the successful application of tissue engineering and regenerative medicine strategies. Optimising culture conditions for the pre-differentiation of MSCs is a key goal for the research community, and this has included a number of different approaches, one of which is the use of mechanical stimuli. Mesenchymal tissues are subjected to mechanical stimuli in vivo and terminally differentiated cells from the mesenchymal lineage respond to mechanical stimulation in vivo and in vitro. MSCs have also been shown to be highly mechanosensitive and this may present an ideal method for controlling MSC differentiation. Here we present an overview of the response of MSCs to various mechanical stimuli, focusing on their differentiation towards the mesenchymal tissue lineages including bone, cartilage, tendon/ligament, muscle and adipose tissue. More research is needed to elucidate the complex interactions between biochemically and mechanically stimulated differentiation pathways.
Delaine-Smith, Robin M.; Reilly, Gwendolen C.
Hematopoietic stem cell transplantation (HSCT) includes bone marrow, peripheral blood, cord blood, autologous, allogeneic, related or unrelated. These transplants have two main roles in cancer treatment, i.e., supportive treatment for marrow toxicity and immunotherapy for cancer cells. HSCT has also severe adverse reaction such as, bacterial fungal or viral infection by neutropenia, or graft versus host disease by the replacement of immune system. In autologous HSCT the main role is to prevent severe marrow toxicity which enables extreme high dose of anticancer drug administration. In allogeneic HSCT the main roles become both, support for marrow toxicity and immunotherapy, which possibly complicated with immunological adverse reactions. In mini-transplant or allogeneic transplant with reduced intensity, the main role is immunotherapy. These three kinds of transplants have each own indication and conducted in 17,472 patients till 2001 in Japan. PMID:12806959
Methods and systems for a) identifying and isolating stem cells, b) assessing mitochondrial distribution and structure in living cells and c) performing fluorescence microscopy on living cells while the cells remain within a condition-controlled cell culture chamber.
Stem cell research has received considerable attention since the discovery that adult stem cells have the capacity to form many different tissue types. Stem cells are a booming field for the research and have been extensively studied in the field of medicine, as well as dentistry. Their application in oncology has been a boon to many of the patients. Dental stem cells have been novel approach to treat diseases like periodontitis, dental caries and many more. Their potential uses in dentistry have provided a new generation of treatments for dental diseases and stem cells have become the focus in dental research. This review highlights about the biology, sources and potential applications of stem cells in dentistry with emphasis on a dentist's role in enabling both medical and dental applications using stem cells from teeth.
Shilpa, P.S.; Kaul, Rachna; Sultana, Nishat; Bhat, Suraksha
A current explanation for development of chronic renal injury is the imbalance between injurious mechanism and regenerative repair. The possibility that stem cells contribute to the repair of glomerular and tubular damage is of great interest for basic and translational research. Endogenous bone marrow-derived stem cells have been implicated in the repair of renal tissue, although the lineage of stem
Benedetta Bussolati; Peter Viktor Hauser; Raquel Carvalhosa; Giovanni Camussi
Only a small number of cells in adult tissues (the stem cells) possess the ability to self-renew at every cell division, while producing differentiating daughter cells to maintain tissue homeostasis for an organism's lifetime. The Drosophila ovary harbors three different types of stem cell populations (germline stem cell (GSC), somatic stem cell (SSC) and escort stem cell (ESC)) located in
Dániel Kirilly; Ting Xie
Stem cells maintain homeostasis in adult tissues via self-renewal and generation of terminally differentiated cells. Alterations in this intricate balance can result in disease. It has become increasingly evident that cancer can be initiated at the level of stem cells. Therefore, understanding what causes stem cells to become cancerous may lead to new therapeutic approaches. Multiple signaling pathways ultimately affect stem cell survival and proliferation, thus maintaining homeostasis in the gut. Changes in these pathways could perturb normal stem cell behavior, leading to cancerous stem cells. In addition, cancerous stem cells show resistance to current therapies and may lead to a dangerous selection process resulting in recurrence and metastasis. Genomic instability, the driving force of mutation and resistance, may give cancerous stem cells an adaptive advantage, especially when subjected to cancer therapies. Targeting the unique characteristics of cancerous stem cells to promote either terminal differentiation or destruction would effectively eradicate cancer and improve patient care and survival.
Vasculogenesis and angiogenesis are the major forms of blood vessel formation. Angiogenesis is the process where new vessels grow from pre-existing blood vessels, and is very important in the functional recovery of pathological conditions, such as wound healing and ischemic heart diseases. The development of better animal model and imaging technologies in past decades has greatly enriched our understanding on vasculogenesis and angiogenesis processes. Hypoxia turned out to be an important driving force for angiogenesis in various ischemic conditions. It stimulates expression of many growth factors like vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor, which play critical role in induction of angiogenesis. Other cellular components like monocytes, T cells, neutrophils, and platelets also play significant role in induction and regulation of angiogenesis. Various stem/progenitor cells also being recruited to the ischemic sites play crucial role in the angiogenesis process. Pre-clinical studies showed that stem/progenitor cells with/without combination of growth factors induce neovascularization in the ischemic tissues in various animal models. In this review, we will discuss about the fundamental factors that regulate the angiogenesis process and the use of stem cells as therapeutic regime for the treatment of ischemic diseases. PMID:22038301
Lu, Jingwei; Pompili, Vincent J; Das, Hiranmoy
Parkinson's disease is the second most common neurological condition, behind dementia, for which there is currently no cure. A promising curative treatment approach is cell replacement therapy, which involves the introduction of new dopaminergic cells into a degenerative Parkinson's disease brain. The future progression of this field into a clinically viable treatment option is reliant on generating replacement dopaminergic cells. Furthermore, as the ability of transplanted dopaminergic neurons to form connections with host tissue is dependent on where the cells are derived from, the replacement dopaminergic cells will need to be phenotypically similar to substantia nigra dopaminergic neurons. This article focuses on how developmental transcription factors have been utilized to assist the progression of stem cell therapies for Parkinson's disease. Key transcription factor-mediated stages of substantia nigra dopaminergic neuronal development is described in the belief that a comprehensive understanding of this specific dopaminergic differentiation pathway is necessary for the progression of successful cell therapies for Parkinson's disease. PMID:20455654
Stem cells possess the ability to self-renew by symmetric divisions and, under certain circumstances, differentiate to a committed\\u000a lineage by asymmetric cell divisions. Depending on the origin, stem cells are classified as either embryonic or adult. Embryonic\\u000a stem cells are obtained from the inner cell mass of the blastocyst, a structure that appears during embryonic development\\u000a at day 6 in
E. Roche; R. Enseńat-Waser; J. A. Reig; J. Jones; T. León-Quinto; B. Soria
The shortage of organ donors for regenerative medicine has stimulated research on stem cells as a potential resource for cell-based\\u000a therapy. Stem cells have been used widely for regenerative medicine applications. The development of innovative methods to\\u000a generate stem cells from different sources suggests that there may be new alternatives for cell-based therapies. Here, we\\u000a provide an overview of human
Jennifer Hipp; Anthony Atala
Abstract There has been a growing ,interest in using ,endothelial cells for therapeutic purposes. This interest has led to exploring ,the use of endothelial ,progenitor cells isolated from human,embryonic ,stem cells. Embryonic ,stem cells are advantageous ,when ,compared with other endothelial cell origin, due to their high proliferation capability, pluripotency, and low immunogenity. However, there remain many challenges and obstacles
Shulamit Levenberg; Janet Zoldan; Yaara Basevitch; Robert Langer
Recently, various human tumors have been shown to contain cancer stem cells. These cells, although rare, appear to be the only cells that can regenerate tumor and mediate metastasis. Therefore, these rare cancer stem cells may be the only cells that actua...
Glioma-initiating cells/glioma stem cells (GIC/GSCs) are grown in vitro using a cumbersome and inefficient spheroid assay. In this issue of Cell Stem Cell, Pollard and coworkers present a protocol for the efficient derivation of GIC/GSC lines that may greatly improve the isolation and the potential clinical application of these cells. PMID:19497271
Woolard, Kevin; Fine, Howard A
|These are interesting days in the scientific, social, and political debates about human embryonic stem cell research. Pluripotent stem cells--cells that can, in principle, give rise to the body's full range of cell types--were previously derivable only from human embryos that were destroyed in the process. Now, a variety of somatic cell types…
Hurlbut, J. Benjamin; Robert, Jason Scott
Recent advancement in developmental biology has led to the discovery of immature mesenchymal stem cells in bone marrow and several established organs. The therapeutic potentials of such stem cells for treating serious diseases constitute a major rationale for every research effort, and clinical trials for replacing some damaged tissues such as cartilage are currently under way. Although the feasibility of
Takahito Ito; Akira Suzuki; Masaru Okabe; Enyu Imai; Masatsugu Hori
Stem cell research, if successful, could provide a means of replacing damaged tissue in patients with diabetes. Controversially, the best stem cells for research and possible therapies seem to be those harvested from embryos, cloned or otherwise. As a result the morality of undertaking such research is hotly contested with vocal champions both for and against this work. To help
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.
Clarke, Diana L.; Johansson, Clas B.; Wilbertz, Johannes; Veress, Biborka; Nilsson, Erik; Karlström, Helena; Lendahl, Urban; Frisén, Jonas
Stem cells are characterized by their dual ability for self-renewal and differentiation, potentially yielding large numbers of cells that can be used in cell therapy and tissue engineering for repairing devastating diseases. Attaining control over stem cell fate decision in culture is a great challenge since these cells integrate a complex array of "niche" signals, which regulate their fate. Given this, the recent findings that synthetic microenvironments can be designed to gain some level of control over stem cell fate are encouraging. This chapter provides an overview of the current state and knowledge of the design of synthetic microenvironments bio-inspired by the adult stem cell niche. We describe the biomaterials used for reconstituting the niche, highlighting the bioengineering principles used in the process. Such synthetic microenvironments constitute powerful tools for elucidating stem cell regulatory mechanisms that should fuel the development of advanced culture systems with accurate regulation of stem cell fate. PMID:21975955
Re'em, Tali; Cohen, Smadar
Honour Index (HoI), a method to evaluate research performance within different research fields, was derived from the impact\\u000a factor (IF). It can be used to rate and compare different categories of journals. HoI was used in this study to determine\\u000a the scientific productivity of stem cell research in the Asian Four Dragons (Hong Kong, Singapore, South Korea and Taiwan)\\u000a from
Y. S. Ho; C. H. Chiu; T. M. Tseng; W. T. Chiu
Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs. PMID:22774232
Sampieri, Katia; Fodde, Riccardo
BackgroundMammary stem cells are maintained within specific microenvironments and recruited throughout lifetime to reconstitute de novo the mammary gland. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the
Shuxian Jiang; Byeong-Chel Lee; Yigong Fu; Shalom Avraham; Bing Lim; Hava Karsenty Avraham
Many cancers seem to depend on a small population of 'cancer stem cells' for their continued growth and propagation. The leukaemia stem cell (LSC) was the first such cell to be described. The origins of these cells are controversial, and their biology — like that of their normal-tissue counterpart, the haematopoietic stem cell (HSC) — is still not fully elucidated.
Brian J. P. Huntly; D. Gary Gilliland
The concept of the adult tissue stem cell is fundamental to models of persistent renewal in functionally post-mitotic tissues. Although relatively ignored by stem cell biology, skeletal muscle is a prime example of an adult tissue that can generate terminally differentiated cells uniquely specialized to carry out tissue-specific functions. This capacity is attributed to satellite cells, a population of undifferentiated,
Peter S. Zammit; Jonathan R. Beauchamp
The following on esophageal stem cells and 3D-cell culture models contains commentaries on metaplasia through transdifferentiation and through stem cells; transcription factors that may determine an intestinal-like phenotype; the?in vitro, organotypic cell culture models; and the role of stem cells in Barrett's esophagus and its dysplastic progression. PMID:21950821
Souza, Rhonda F; Schwartz, Robert E; Mashimo, Hiroshi
The pituitary is the master endocrine gland of the body. It undergoes many changes after birth, and these changes may be mediated by the differentiation of pituitary stem cells. Stem cells in any tissue source must display (1) pluripotent capacity, (2) capacity for indefinite self-renewal, and (3) a lack of specialization. Unlike neural stem cells identified in the hippocampus and subventricular zone, pituitary stem cells are not associated with one specific cell type. There are many major candidates that are thought to be potential pituitary stem cell sources. This article reviews the evidence for each of the major cell types and discuss the implications of identifying a definitive pituitary stem cell type. PMID:23423660
Nassiri, Farshad; Cusimano, Michael; Zuccato, Jeff A; Mohammed, Safraz; Rotondo, Fabio; Horvath, Eva; Syro, Luis V; Kovacs, Kalman; Lloyd, Ricardo V
Patients with congestive heart failure (CHF) that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a) increasing stem cell migration to the heart; b) augmenting stem cell activity; and c) combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells.
A current explanation for development of chronic renal injury is the imbalance between injurious mechanism and regenerative repair. The possibility that stem cells contribute to the repair of glomerular and tubular damage is of great interest for basic and translational research. Endogenous bone marrow-derived stem cells have been implicated in the repair of renal tissue, although the lineage of stem cells recruited has not been determined. If endogenous bone marrow-derived stem cells repopulate injured nephrons directly or act indirectly over a paracrine/endocrine mechanism remains also controversial. Therapeutic administration of exogenous bone marrow derived stem cells in animal models of acute renal injury suggests that a stem cell-based therapy may improve the recovery of both glomerular and tubular compartments. Whereas the therapeutic benefit of sorted hematopoietic stem cells remains uncertain, several studies showed a beneficial effect of mesenchymal stem cell administration in models of acute tubular injury and of endothelial progenitors in acute glomerular injury. Recent studies demonstrate the presence of resident stem cells within the adult kidney. These cells are capable, when injected in animals with acute tubular injury, to localize to renal compartments and contribute to regeneration. This review summarizes the current literature on the physiological role of endogenous stem cells in renal regeneration and on the therapeutic potential of exogenous stem cell administration. Moreover, critical points that still need clarification, such as the homing mechanisms of stem cells to injured tissue, the secreted factors underlying the paracrine/endocrine mechanisms and the long-term behaviour of in vivo administered stem cells, are discussed. PMID:19149624
Bussolati, Benedetta; Hauser, Peter Viktor; Carvalhosa, Raquel; Camussi, Giovanni
Somatic cell nuclear transfer or therapeutic cloning has provided great hope for stem cell-based therapies. However therapeutic cloning has been experiencing both ethical and technical difficulties. Recent breakthrough studies using a combination of four factors to reprogram human somatic cells into pluripotent stem cells without using embryos or eggs led to an important revolution in stem cell research. Comparative analysis of human induced pluripotent stem cells and human embryonic stem cells using assays for morphology, cell surface marker expression, gene expression profiling, epigenetic status, and differentiation potential revealed a remarkable degree of similarity between these two pluripotent stem cell types. This mini-review summarizes these ground-breaking studies. The advance in reprogramming will enable the creation of patient-specific stem cell lines to study various disease mechanisms. The created cellular models will provide valuable tools for drug discovery. Furthermore, this reprogramming system provides great potential to make customized patient-specific stem cell therapy with economical feasibility.
Neural stem cell (NSC) transplantation has been proposed as a future therapy for neurodegenerative disorders. However, NSC transplantation will be hampered by the limited number of brain donors and the toxicity of immunosuppressive regimens that might be needed with allogeneic transplantation. These limitations may be avoided if NSCs can be generated from clinically accessible sources, such as bone marrow (BM) and peripheral blood samples, that are suitable for autologous transplantation. We report here that NSCs can be generated from human BM-derived mesenchymal stem cells (MSCs). When cultured in NSC culture conditions, 8% of MSCs were able to generate neurospheres. These MSC-derived neurospheres expressed characteristic NSC antigens, such as nestin and musashi-1, and were capable of self-renewal and multilineage differentiation into neurons, astrocytes, and oligodendrocytes. Furthermore, when these MSC-derived neurospheres were cocultured with primary astrocytes, they differentiate into neurons that possess both dendritic and axonal processes, form synapses, and are able to fire tetrodotoxin-sensitive action potentials. When these MSC-derived NSCs were switched back to MSC culture conditions, a small fraction of NSCs (averaging 4–5%) adhered to the culture flasks, proliferated, and displayed the morphology of MSCs. Those adherent cells expressed the characteristic MSC antigens and regained the ability to differentiate into multiple mesodermal lineages. Data presented in this study suggest that MSCs contain a small fraction (averaging 4–5%) of a bipotential stem cell population that is able to generate either MSCs or NSCs depending on the culture conditions.
Fu, Lijuan; Zhu, Lunjian; Huang, Yu; Lee, Tsung D.; Forman, Stephen J.
In recent years, somatic stem cells have been heralded as potential therapeutic agents to address a large number of degenerative diseases. Yet, in order to rationally utilize these cells as effective therapeutic agents, and/or improve treatment of stem-cell-associated malignancies such as leukemias and carcinomas, a better understanding of the basic biological properties of stem cells needs to be acquired. A major limitation in the study of somatic stem cells lies in the difficulty of accessing and studying these cells in vivo. This barrier is further compounded by the limitations of in vitro culture systems, which are unable to emulate the microenvironments in which stem cells reside and which are known to provide critical regulatory signals for their proliferation and differentiation. Given the complexity of vertebrate adult somatic stem cell populations and their relative inaccessibility to in vivo molecular analyses, the study of somatic stem cells should benefit from analyzing their counterparts in simpler model organisms. In the past, the use of Drosophila or C. elegans has provided invaluable contributions to our understanding of genes and pathways involved in a variety of human diseases. However, stem cells in these organisms are mostly restricted to the gonads, and more importantly neither Drosophila, nor C. elegans are capable of regenerating body parts lost to injury. Therefore, a simple animal with experimentally accessible stem cells playing a role in tissue maintenance and/or regeneration should be very useful in identifying and functionally testing the mechanisms regulating stem cell activities. The planarian Schmidtea mediterranea is poised to fill this experimental gap. S. mediterranea displays robust regenerative properties driven by an adult, somatic stem cell population capable of producing the ?40 different cell types found in this organism, including the germ cells. Given that all known metazoans depend on stem cells for their survival, it is extremely likely that the molecular events regulating stem cell biology would have been conserved throughout evolution, and that the knowledge derived from studying planarian stem cells could be vertically integrated to the study of vertebrate somatic stem cells. Current efforts, therefore, are aimed at further characterizing the somatic population of planarian stem cells in order to define its suitability as a model system in which to mechanistically dissect the basic biological attributes of metazoans stem cells.
Sanchez Alvarado, Alejandro
Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell–based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson’s disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success.
Joers, Valerie L.; Emborg, Marina E.
Human stem cells are scalable cell populations capable of cellular differentiation. This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells. Such an approach has the potential to improve our understanding of human biology and treating disease. In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases. In recent years, efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own. In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.
Zhou, Wen-Li; Medine, Claire N; Zhu, Liang; Hay, David C
The mammalian subventricular zone (SVZ) has garnered a tremendous amount of attention as a potential source of replacement\\u000a cells for neuronal injury. This zone is highly neurogenic, harbours stem cells and supports long-distance migration. The general\\u000a pattern of activation includes increased proliferation, neurogenesis and emigration towards the injury. Intrinsic transcription\\u000a factors and environmental signalling molecules are rapidly being discovered that
Yongsoo Kim; Francis G. Szele
Millions of people world over suffer visual disability due to retinal dystrophies which can be age-related or a genetic disorder resulting in gradual degeneration of the retinal pigmented epithelial (RPE) cells and photoreceptors. Therefore, cell replacement therapy offers a great promise in treating such diseases. Since the adult retina does not harbour any stem cells, alternative stem cell sources like the embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer a great promise for generating different cell types of the retina. Here, we report the derivation of four iPSC lines from mouse embryonic fibroblasts (MEFs) using a cocktail of recombinant retroviruses carrying the genes for Oct4, Sox2, Klf4 and cMyc. The iPS clone MEF-4F3 was further characterized for stemness marker expression and stable reprogramming by immunocytochemistry, FACS and RT-PCR analysis. Methylation analysis of the nanog promoter confirmed the reprogrammed epigenetic state. Pluripotency was confirmed by embryoid body (EB) formation and lineage-specific marker expression. Also, upon retinal differentiation, patches of pigmented cells with typical cobble-stone phenotype similar to RPE cells are generated within 6 weeks and they expressed ZO-1 (tight junction protein), RPE65 and bestrophin (mature RPE markers) and showed phagocytic activity by the uptake of fluorescent latex beads. PMID:23385820
Mekala, Subba Rao; Vauhini, Vasundhara; Nagarajan, Usha; Maddileti, Savitri; Gaddipati, Subhash; Mariappan, Indumathi
Currently, there is no effective treatment for photoreceptor degeneration, the most common cause of blindness caused by diseases like retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy. Two promising approaches include cell therapy to replace degenerating cells and neuroprotection to rescue affected cells from premature death. Determination of the potential of embryonic stem (ES) cells to differentiate into photoreceptors will provide reagents for both approaches. First, neural progenitors with retinal potential will be available in unlimited supply to test the efficacy of cell therapy; second, the controlled differentiation of ES cells into photoreceptors, in addition to providing cells to replace degenerating photoreceptors, will offer a robust in vitro model of photoreceptor differentiation for better understanding of degenerative processes and screening of neuroprotective drugs/reagents. In addition, it will allow the identification of genes (gene discovery) that play critical roles in photoreceptor differentiation and degeneration. Here, we describe the protocol to promote differentiation of the mouse ES cell-derived neural progenitors into retinal cells, specifically the rod photoreceptors. PMID:16846039
Zhao, Xing; Liu, Jianuo; Ahmad, Iqbal
\\u000a Recently a large amount of new data on the plasticity of stem cells of various lineages have emerged, providing new perspectives\\u000a especially for the therapeutic application of adult stem cells. Previously unknown possibilities of cell differentiation beyond\\u000a the known commitment of a given stem cell have been described using keywords such as “blood to liver,” or “bone to brain.”\\u000a Controversies
Ina Gruh; Ulrich Martin
This article will provide an updated review of spermatogonial stem cells and their role in maintaining the spermatogenic lineage. Experimental tools used to study spermatogonial stem cells (SSCs) will be described, along with research using these tools to enhance our understanding of stem cell biology and spermatogenesis. Increased knowledge about the biology of SSCs improves our capacity to manipulate these cells for practical application. The chapter concludes with a discussion of future directions for fundamental investigation and practical applications of SSCs.
Phillips, Bart T.; Gassei, Kathrin; Orwig, Kyle E.
In recent years, stem cells have been heralded as potential therapeutic agents to address a large number of degenerative diseases. Yet, in order to rationally utilize these cells as effective therapeutic agents, and\\/or improve treatment of stem-cell-associated malignancies such as leukemias and carcinomas, a better understanding of the basic biological properties of stem cells needs to be acquired. A major
Alejandro Sánchez Alvarado
Summary Many recent experimental findings on heterogeneity, flexibility, and plasticity of tissue stem cells are challenging the classical stem cell concept of a pre-defined, cell-intrinsic developmental program. Moreover, a number of these results are not consistent with the paradigm of a hierarchically structured stem cell population with a uni-directional development. Non-hierarchical, self-organizing systems provide a more elegant and comprehensive alternative
Ingo Roeder; Joerg Galle; Markus Loeffler
Rarely has so much interest from the lay public, government, biotechnology industry, and special interest groups been focused on the biology and clinical applications of a single type of human cell as is today on stem cells, the founder cells that sustain many, if not all, tissues and organs in the body. Granting organizations have increasingly targeted stem cells as
Stephen J Szilvassy
Stem cells are present in all self-reviewing tissues and have unique properties. The ocular surface is made up of two distinct types of epithelial cells, constituting the conjunctival and the corneal epithelia. These epithelia are stratified, squamous and non-keratinized. Although anatomically continuous with each other at the corneoscleral limbus, the two cell phenotypes represent quite distinct subpopulations. The stem cells
Virender S. Sangwan
The induction of pluripotency in somatic cells is widely considered as a major breakthrough in regenerative medicine, because this approach provides the basis for individualized stem cell-based therapies. Moreover, with respect to cell transplantation and tissue engineering, expertise from bioengineering to transplantation medicine is now meeting basic research of stem cell biology.
Cantz, Tobias; Martin, Ulrich
Human CD34+ hematopoietic stem and progenitor cells are capable of maintaining a life-long supply of the entire spectrum of blood cells dependent on systemic needs. Recent studies suggest that hematopoietic stem cells are, beyond their hematopoietic potential, able to differentiate into nonhematopoietic cell types, which could open novel avenues in the field of cellular therapy. Here, we concentrate on the
Ulrich Steidl; Ralf Kronenwett; Simona Martin; Rainer Haas
Summary Techniques are described for the culture of murine embryonic stem cells in the absence of heterologous feeder cells and for the induction of differentiation programs. The regulatory factor differentiation inhibiting activity\\/ leukaemia inhibitory factor (DIA\\/LIF) is produced at high concentration by transient expression in Cos cells and is used to suppress stem cell differentiation by addition to the culture
Austin G. Smith
Previous methods for culturing human embryonic stem cells have required either fibroblast feeder cells or a medium which has been exposed to fibroblast feeder cells in order to maintain the stem cells in an undifferentiated state. It has now been found th...
J. A. Thomson T. Ludwig
Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here
K. Kim; A. Doi; B. Wen; K. Ng; R. Zhao; P. Cahan; J. Kim; M. J. Aryee; H. Ji; L. I. R. Ehrlich; A. Yabuuchi; A. Takeuchi; K. C. Cunniff; H. Hongguang; S. McKinney-Freeman; O. Naveiras; T. J. Yoon; R. A. Irizarry; N. Jung; J. Seita; J. Hanna; P. Murakami; R. Jaenisch; R. Weissleder; S. H. Orkin; I. L. Weissman; A. P. Feinberg; G. Q. Daley
Mammary gland (MG) stem cells, like stem cells in other tissues, are quiescent cells that retain an enormous capacity for self-renewal and differentiation throughout many years of life. These primitive cells are thought to be a likely target for tumorigen...
M. Goodell J. Rosen
In tissue engineering fields, recent interest has been focused on stem cell therapy to replace or repair damaged or worn-out tissues due to congenital abnormalities, disease, or injury. In particular, the repair of articular cartilage degeneration by stem cell-based tissue engineering could be of enormous therapeutic and economic benefit for an aging population. Bone marrow-derived mesenchymal stem cells (MSCs) that can induce chondrogenic differentiation would provide an appropriate cell source to repair damaged cartilage tissues; however, we must first understand the optimal environmental conditions for chondrogenic differentiation. In this review, we will focus on identifying the best combination of MSCs and functional extracellular matrices that provides the most successful chondrogenesis.
Seo, Seogjin; Na, Kun
\\u000a Murine embryonic stem (mES) cells are permanent tissue culture cell lines isolated from explanted blastocysts. mES cells share\\u000a an unusual set of properties with the stem cells of germ cell tumours (EC cells). Both cell types can be cultured under conditions\\u000a in which they cycle indefinitely, or in which they terminally differentiate into a variety of specialised cells. When undifferentiated
Jim McWhir; Alison Thomson; Virginie Sottile
This paper argues that stem cells, with their ability to replace damaged tissues and organs may open new horizons for prolonging-life therapies. The article suggests that stopping this research is improbable and also undesirable, because if successful, millions of people will greatly benefit. On the other hand, this progression in curing disease may result in prolonging life, possibly indefinitely. This paper explores notions of human indefinitely prolonged life (IPL)--assuming that IPL maintains people's health and full capabilities--and suggests that existing claims against IPL, such as overpopulation, reduced brain capacity and possible personal boredom, do not justify avoiding IPL when, and if it becomes available. Nor does global justice require people from developed societies to give up their lives. It concludes however, that, although we should not prevent people from living longer lives, new schemes of morality should be developed under this perspective. PMID:17476939
Recent studies suggest that extrafollicular dermal melanocyte stem cells (MSCs) persist after birth in the superficial nerve sheath of peripheral nerves and give rise to migratory melanocyte precursors when replacements for epidermal melanocytes are needed on the basal epidermal layer of the skin. If a damaged MSC or melanocyte precursor can be shown to be the primary origin of melanoma, targeted identification and eradication of it by antibody-based therapies will be the best method to treat melanoma and a very effective way to prevent its recurrence. Transcription factors and signaling pathways involved in MSC self-renewal, expansion and differentiation are reviewed. A model is presented to show how the detrimental effects of long-term UVA/UVB radiation on DNA and repair mechanisms in MSCs convert them to melanoma stem cells. Zebrafish have many advantages for investigating the role of MSCs in the development of melanoma. The signaling pathways regulating the development of MSCs in zebrafish are very similar to those found in humans and mice. The ability to easily manipulate the MSC population makes zebrafish an excellent model for studying how damage to MSCs may lead to melanoma.
Hoerter, James D.; Bradley, Patrick; Casillas, Alexandria; Chambers, Danielle; Denholm, Carli; Johnson, Kimberly; Weiswasser, Brandon
Human amniotic fluid cells have been used traditionally as a diagnostic tool for genetic anomalies. More recently it has been recognized that amniotic fluid contains populations of stem cells. Mesenchymal stem cells (AFMSC) were first to be described. These cells are able to differentiate towards mesodermal lineages. More recently cells with broader potential, defined as amniotic fluid stem cells (AFSC), were also isolated. They have intermediate characteristics between embryonic and adult stem cells and are able to differentiate into lineages representative of all three germ layers but unlike ES cells they do not form tumours in vivo. Furthermore, AFSC have been reverted to functional pluripotency in a transgene-free approach using an epigenetics modifier. These characteristics, together with absence of ethical issues concerning their employment, have made stem cells from amniotic fluid a promising candidate for cell therapy and tissue engineering. PMID:23157178
Abdulrazzak, Hassan; De Coppi, Paolo; Guillot, Pascale V
Acute renal failure and tubular cell loss as a result of ischemia constitute major challenges in renal pathophysiology. Increasing evidence suggests important roles for bone marrow stem cells in the regeneration of renal tissue after injury. This study investigated whether the enhanced availability of hematopoietic stem cells, induced by stem cell factor and granulocyte colony-stimulating factor, to the injured kidney
Geurt Stokman; Jaklien C. Leemans; Nike Claessen; Jan J. Weening; Sandrine Florquin
The use of stems cells in tendon repair is of particular interest given the frequency of tendon injuries worldwide together with the technical difficulty often encountered when repairing or augmenting tendons. Stems cells have the capability to differentiate into a variety of different cell types including osteocytes and tenocytes, and if normal architecture of damaged tendon (either macroscopic or microscopic) could be restored, this would significantly improve the management of patients with these injuries. There is already encouraging research on the use of stems cells clinically although considerable further work is required to improve knowledge and clinical applications of stem cells in tissue engineering.
MacLean, S.; Khan, W. S.; Malik, A. A.; Snow, M.; Anand, S.
Transplantation of stem cells or their derivatives, and mobilization of endogenous stem cells in the adult brain, have been proposed as future therapies for various brain disorders such as Parkinson's disease and stroke. In support, recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. However, from a clinical perspective, the development of stem cell-based therapies for brain diseases is still at an early stage. Many basic issues remain to be solved and we need to move forward with caution and avoid scientifically ill-founded trials in patients. We do not know the best stem cell source, and research on embryonic stem cells and stem cells from embryonic or adult brain or from other tissues should therefore be performed in parallel. We need to understand how to control stem cell proliferation and differentiation into specific cell types, induce their integration into neural networks, and optimize the functional recovery in animal models closely resembling the human disease. All these scientific efforts are clearly justified because, for the first time, there is now real hope that we in the future can offer patients with currently intractable diseases effective cell-based treatments to restore brain function. PMID:16221169
Lindvall, Olle; Kokaia, Zaal
This is a comprehensive review on label retaining cells (LRC) in epidermal development and homeostasis. The precise in vivo\\u000a identification and location of epidermal stem cells is a crucial issue in cutaneous biology. We discuss here the following\\u000a problems: (1) Identification and location of LRC in the interfollicular epithelium and hair follicle; (2) The proliferative\\u000a potential of LRC and their
Vasily V. Terskikh; Andrey V. Vasiliev; Ekaterina A. Vorotelyak
Cell lines and genetically modified single cell organisms have been considered patentable subjects for the last two decades. However, despite the technical patentability of genes and stem cell lines, social and legal controversy concerning their 'ownership' has surrounded stem cell research in recent years. Some granted patents on stem cells with extremely broad claims are casting a shadow over the commercialization of these cells as therapeutics. However, in spite of those early patents, the number of patent applications related to stem cells is growing exponentially. Both embryonic and adult stem cells have the ability to differentiate into several cell lineages in an organism as a result of specific genetic programs that direct their commitment and cell fate. Genes that control the pluripotency of stem cells have been recently identified and the genetic manipulation of these cells is becoming more efficient with the advance of new technologies. This review summarizes some of the recent published patents on pluripotency genes, gene transfer into stem cells and genetic reprogramming and takes the hematopoietic and embryonic stem cell as model systems. PMID:19075916
Martin-Rendon, Enca; Blake, Derek J
Summary Several human organs are not capable of functional regeneration following a tissue defect and react with scar formation. In stem cell transplantation, undifferentiated or partly differentiated precursor cells are applied to defective tissue for therapeutic regeneration. After promising preclinical investigations, the transplantation of autologous stem cells for myocardial infarction treatment is being transferred to clinical use. Mesenchymal stem cells
Matthias Siepe; Claudia Heilmann; Patrick von Samson; Philippe Menasché; Friedhelm Beyersdorf
Mesenchymal stem cells (MSCs) are considered to be a promising platform for cell and gene therapy for a variety of diseases. First, in the field of hematopoietic stem cell transplantation, there are two applications of MSCs: 1) the improvement of stem cell engrafting and the acceleration of hematopoietic reconstitution based on the hematopoiesis-supporting ability; and 2) the treatment of severe
Keiya Ozawa; Kazuya Sato; Iekuni Oh; Katsutoshi Ozaki; Ryosuke Uchibori; Yoko Obara; Yuji Kikuchi; Takayuki Ito; Takashi Okada; Masashi Urabe; Hiroaki Mizukami; Akihiro Kume
Stem cells carry the promise to cure a broad range of diseases and injuries, from diabetes, heart and muscular diseases, to neurological diseases, disorders and injuries. Significant progresses have been made in stem cell research over the past decade; the derivation of embryonic stem cells (ESCs) from human tissues, the development of cloning technology by somatic cell nuclear transfer (SCNT)
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The motor symptoms of PD are caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta of mesencephalon. The causes for death of DA neurons are not well understood, but the strongest risk factor is increasing age. There is no cure currently available for PD, and treatment is limited to management of PD symptoms in patients. Primary DA neurons are virtually unobtainable from living patients and animal studies have proven inadequate for studying the mechanism of PD development. Pluripotent stem cells (PSC) are primary self-renewing cells capable of differentiating into all cell types of an organism, including DA neurons. PSCs represent an abundant source of cells that can be genetically modified or isolated from patients with complex diseases, enabling the production of large quantities of DA neurons for disease modeling, drug screening, and gene function studies. Furthermore, since PD arises as a result of deterioration of DA neurons in a specific brain region, it has been suggested that a relatively small number of cells could restore normal function. PSCs could provide a source of DA neurons for cell replacement therapy. In this Prospects article, we focus on the development and in vitro derivation of DA neurons from PSCs, as well as current applications of the technological advances, with the emphasis on future directions and efforts in the field. PMID:22807388
Mom?ilovi?, Olga; Montoya-Sack, Justine; Zeng, Xianmin
Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease.
Huff, Carol Ann; Matsui, William
Stem cell research can significantly benefit from recent advances of microfluidics technology. In a rationally designed microfluidics device, analyses of stem cells can be done in a much deeper and wider way than in a conventional tissue culture dish. Miniaturization makes analyses operated in a high-throughput fashion, while controls of fluids help to reconstruct the physiological environments. Through integration with present characterization tools like fluorescent microscope, microfluidics offers a systematic way to study the decision-making process of stem cells, which has attractive medical applications. In this paper, recent progress of microfluidics devices on stem cell research are discussed. The purpose of this review is to highlight some key features of microfluidics for stem cell biologists, as well as provide physicists/engineers an overview of how microfluidics has been and could be used for stem cell research. PMID:23336098
Zhang, Qiucen; Austin, Robert H
All organisms depend on stem cells for their survival. As a result, stem cells may be a prerequisite for the evolution of specific characteristics in organisms that include regeneration, multicellularity and coloniality. Stem cells have attracted the attention of biologists and medical scientists for a long time. These provide materials for regenerative medicine. We review in this paper, the link between modern stem cell research and early studies in ancient organisms. It also outlines details on stem cells in the light of evolution with an emphasis on their regeneration potential, coloniality and multicellularity. The information provided might be of use to molecular biologists, medical scientists and developmental biologists who are engaged in integrated research involving the stem cells.
Chakraborty, Chiranjib; Agoramoorthy, Govindasamy
In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.
LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J
Research on hepatic stem cells has entered a new era of controversy, excitement, and great expectations. Although adult liver stem cells have not yet been isolated, an enormous repopulating capacity of transplanted mature hepatocytes under conditions of continuous liver injury has been discovered. Stem/progenitor cells from fetal liver have been successfully isolated and transplanted, repopulating up to 10% of normal liver. However, progenitor cell lines from adult and embryonic liver have not shown significant repopulating activity. Intensive research on embryonic stem cells has revealed the first promising attempts to use these cells as a source of hepatic progenitors. Conditions for their differentiation in vitro, isolation of purified hepatic progenitor cells, and liver repopulation are currently being evaluated. Multilineage adult progenitor cells of mesenchymal origin from bone marrow, muscle, and brain may turn out to be the long-sought primitive potential stem cells remaining in adult tissues. PMID:14722812
Dabeva, Mariana D; Shafritz, David A
Cell-replacement therapy promises a useful tool to regen- erate compromised brain tissue, but the interaction between grafted cells and host tissues is not well under- stood. In these studies, the fates of neuroectodermal stem cells were compared in 'healthy' or damaged mouse fore- brains. One-cell derived, fluorescent GFP-4C neural stem cells were implanted into normal and cold-lesioned mouse cortices. The
V. A. Ágoston; A. Zádori; K. Demeter; Z. Nagy; E. Madarász
Radiotherapy represents the most effective nonsurgical treatments for gliomas. Yet, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we showed that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) rendered the glioma stem cells more sensitive to radiation at clinically relevant doses. GSIs enhanced radiation-induced cell death and impaired clonogenic survival of glioma stem cells, but not non-stem glioma cells. Similarly, knockdown of Notch1 or Notch2 increased radiosensitivity of glioma stem cells. The specificity of the radiosensitizing effects of GSIs was confirmed by expression of the constitutively active intracellular domains of Notch1 or Notch2 that protected glioma stem cells against radiation. Notch inhibition with GSIs did not alter the DNA damage response of glioma stem cells following radiation, but rather impaired radiation-induced Akt activation and upregulated levels of the truncated apoptotic isoform of Mcl-1 (Mcl-1s). Taken together, our results suggest a critical role of Notch to promote radioresistance of glioma stem cells. Inhibition of Notch signaling holds promise to improve the efficiency of current radiotherapy in glioma treatment.
Wang, Jialiang; Wakeman, Timothy P.; Latha, Justin D.; Hjelmeland, Anita B.; Wang, Xiao-Fan; White, Rebekah R.; Rich, Jeremy N.; Sullenger, Bruce A.
Radiotherapy represents the most effective nonsurgical treatments for gliomas. However, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we show that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) renders the glioma stem cells more sensitive to radiation at clinically relevant doses. GSIs enhance radiation-induced cell death and impair clonogenic survival of glioma stem cells but not non-stem glioma cells. Expression of the constitutively active intracellular domains of Notch1 or Notch2 protect glioma stem cells against radiation. Notch inhibition with GSIs does not alter the DNA damage response of glioma stem cells after radiation but rather reduces Akt activity and Mcl-1 levels. Finally, knockdown of Notch1 or Notch2 sensitizes glioma stem cells to radiation and impairs xenograft tumor formation. Taken together, our results suggest a critical role of Notch signaling to regulate radioresistance of glioma stem cells. Inhibition of Notch signaling holds promise to improve the efficiency of current radiotherapy in glioma treatment. PMID:19921751
Wang, Jialiang; Wakeman, Timothy P; Lathia, Justin D; Hjelmeland, Anita B; Wang, Xiao-Fan; White, Rebekah R; Rich, Jeremy N; Sullenger, Bruce A
Stem cells of the adult vertebrate intestine (ISCs) are responsible for the continuous replacement of intestinal cells, but also serve as site of origin of intestinal neoplasms. The interaction between multiple signaling pathways, including Wnt/Wg, Shh/Hh, BMP, and Notch, orchestrate mitosis, motility, and differentiation of ISCs. Many fundamental questions of how these pathways carry out their function remain unanswered. One approach to gain more insight is to look at the development of stem cells, to analyze the "programming" process which these cells undergo as they emerge from the large populations of embryonic progenitors. This review intends to summarize pertinent data on vertebrate intestinal stem cell biology, to then take a closer look at recent studies of intestinal stem cell development in Drosophila. Here, stem cell pools and their niche environment consist of relatively small numbers of cells, and questions concerning the pattern of cell division, niche-stem cell contacts, or differentiation can be addressed at the single cell level. Likewise, it is possible to analyze the emergence of stem cells during development more easily than in vertebrate systems: where in the embryo do stem cells arise, what structures in their environment do they interact with, and what signaling pathways are active sequentially as a result of these interactions. Given the high degree of conservation among genetic mechanisms controlling stem cell behavior in all animals, findings in Drosophila will provide answers that inform research in the vertebrate stem cell field. PMID:22529012
Takashima, Shigeo; Hartenstein, Volker
Bone marrow (BM) contains hematopoietic stem cells, which differentiate into all mature blood cells, and marrow stromal cells\\u000a that provide the microenvironment for hematopoietic stem\\/progenitor cells along with the capability to differentiate into\\u000a mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent studies indicate that adult BM also\\u000a contains cells that can differentiate into nonhematopoietic cells of
Toshio Heike; Tatsutoshi Nakahata
Stem cells have been used routinely for more than three decades to repair tissues and organs damaged by injury or disease, most notably haematopoietic stem cells taken from bone marrow, umbilical cord or, increasingly, from peripheral blood. Other examples, such as grafts of skin to treat severe burns, entail transplantation of stem cells within organized tissue rather than following isolation. The prospect of exploiting stem cells more widely in regenerative medicine was encouraged both by the development of human assisted conception and growing evidence that various adult cells retained greater versatility than had been suspected hitherto. The aim is to employ stem cells as a source of appropriately differentiated cells to replace those lost through physical, chemical or ischaemic injury, or as a result of degenerative disease. This may entail transplantation of just a single type of cell or, more challengingly, require a complex of several different types of cells possessing a defined architecture. Cardiomyocytes, hepatocytes or neuronal cells producing specific transmitters offer promising examples of the former, although how transplanted healthy cells will function in a perturbed tissue environment remains to be established. Recent success in repairing urinary bladder defects with grafts of urothelial and muscle cells seeded on a biodegradable collagen scaffold is an encouraging step towards assembling organs in vitro. Nevertheless, this is still far removed from the level of sophistication required to counter the ever increasing shortfall in supply of kidneys for transplantation. Various problems must be addressed if recent advances in the laboratory are to be translated into clinical practice. In many cases, it has yet to be established that cells derived from adults that retain plasticity are actually stem cells. There is also a pressing need for appropriate assays to ensure that, regardless of source, stem cells maintained in vitro are safe to transplant. Assays currently available for human ES cells are far from ideal. It is, in addition, important to ensure that differentiated cultures are pure and, depending on whether cell renewal is required or to be avoided, retain or lack appropriate stem cells. Neither autografts nor those obtained by so-called 'therapeutic cloning' are options for treating condition with an obvious genetic basis. Moreover, claims that some stem cells are more likely than others to yield successful allografts have yet to be confirmed and explained. PMID:17631439
Gardner, Richard L
The term “stem cell exceptionalism” has been used to characterize the policy response to controversies surrounding human embryonic\\u000a stem cell research. For example, governments and funding agencies have adopted policies governing the derivation and use of\\u000a human embryonic stem cell lines. These policies have effectively served to fill gaps in existing guidelines and regulations\\u000a and signal that scientists are committed
Geoffrey P. Lomax; Steven R. Peckman
Quantitative approaches are essential for the advancement of strategies to manipulate stem cells or their derivatives for\\u000a therapeutic applications. Predictive models of stem cell systems would provide the means to pose and validate non-intuitive\\u000a hypotheses and could thus serve as an important tool for discerning underlying regulatory mechanisms governing stem cell fate\\u000a decisions. In this paper we review the development
Sowmya Viswanathan; Peter W. Zandstra
In recent years, clinical trials with stem cells have taken the emerging field in many new directions. While numerous teams\\u000a continue to refine and expand the role of bone marrow and cord blood stem cells for their vanguard uses in blood and immune\\u000a disorders, many others are looking to expand the uses of the various types of stem cells found
Alan Trounson; Rahul G. Thakar; Geoff Lomax; Don Gibbons
\\u000a The ability to genetically manipulate stem cells is central in our effort to harness their potential. Various genetic approaches\\u000a are now being implemented in human embryonic stem cells with the goal of understanding basic regulatory mechanisms, as well\\u000a as modifying them toward potential therapeutic applications. This chapter will review genetic strategies available for the\\u000a modification of human embryonic stem cells.
Dimitris G. Placantonakis; Mark J. Tomishima; Fabien G. Lafaille; Lorenz Studer
Transplantation of genetically modified hematopoietic stem cells is a