Stem cells hold great promise for pancreatic beta cell replacement therapy for diabetes. In type 1 diabetes, beta cells are mostly destroyed, and in type 2 diabetes beta cell numbers are reduced by 40% to 60%. The proof-of-principle that cellular transplants of pancreatic islets, which contain insulin-secreting beta cells, can reverse the hyperglycemia of type 1 diabetes has been established, and there is now a need to find an adequate source of islet cells. Human embryonic stem cells can be directed to become fully developed beta cells and there is expectation that induced pluripotent stem (iPS) cells can be similarly directed. iPS cells can also be generated from patients with diabetes to allow studies of the genomics and pathogenesis of the disease. Some alternative approaches for replacing beta cells include finding ways to enhance the replication of existing beta cells, stimulating neogenesis (the formation of new islets in postnatal life), and reprogramming of pancreatic exocrine cells to insulin-producing cells. Stem-cell-based approaches could also be used for modulation of the immune system in type 1 diabetes, or to address the problems of obesity and insulin resistance in type 2 diabetes. Herein, we review recent advances in our understanding of diabetes and beta cell biology at the genomic level, and we discuss how stem-cell-based approaches might be used for replacing beta cells and for treating diabetes.
In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive
Vincenzo Silani; Massimo Corbo
Mesenchymal stem cells represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action.
Christ, Bruno; Stock, Peggy
Adult epithelial stem cells are thought to reside in specific niches, where they are maintained by adhesion to stromal cells and by intercellular signals. In niches that harbor multiple adjacent stem cells, such as those maintaining Drosophila germ cells, lost stem cells are replaced by division of neighboring stem cells or reversion of transit cells. We have characterized the Drosophila follicle stem cell (FSC) niche as a model of the epithelial niche to learn whether nonneighboring cells can also generate stem cell replacements. Exactly two stroma-free FSC niches holding single FSCs are located in fixed locations on opposite edges of the Drosophila ovariole. FSC daughters regularly migrate across the width of the ovariole to the other niche before proliferating and contributing to the follicle cell monolayer. Crossmigrating FSC daughters compete with the resident FSC for niche occupancy and are the source of replacement FSCs. The ability of stem cell daughters to target a distant niche and displace its resident stem cell suggests that precancerous mutations might spread from niche to niche within stem cell-based tissues. PMID:18371362
Nystul, Todd; Spradling, Allan
Genetic manipulation of human pluripotent stem cells (hPSCs) provides a powerful tool for modeling diseases and developing future medicine. Recently a number of independent genome-editing techniques were developed, including plasmid, bacterial artificial chromosome, adeno-associated virus vector, zinc finger nuclease, transcription activator-like effecter nuclease, and helper-dependent adenoviral vector. Gene editing has been successfully employed in different aspects of stem cell research such as gene correction, mutation knock-in, and establishment of reporter cell lines (Raya et al., 2009; Howden et al., 2011; Li et al., 2011; Liu et al., 2011b; Papapetrou et al., 2011; Sebastiano et al., 2011; Soldner et al., 2011; Zou et al., 2011a). These techniques combined with the utility of hPSCs will significantly influence the area of regenerative medicine. PMID:22173708
Pan, Huize; Zhang, Weiqi; Zhang, Weizhou; Liu, Guang-Hui
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 amplifying and fully differentiated cells elsewhere in the organism, with positive and negative feedback. This formulation allows graded signals to be turned into all or nothing responses, and shows the importance of looking beyond the niche for understanding how stem cells behave. Using the deterministic version of this framework, we show how competition between different stem cell lines can be analyzed, and under what circumstances stem cells in a niche will be replaced by other stem cells with different phenotypic characteristics. Using the stochastic version of our framework and state dependent life history theory, we show that the optimal behavior of a focal stem cell will involve long periods of quiescence and that a population of identical stem cells will show great variability in the times at which activity occurs; we compare our results with classic ones on quiescence and variability in the hematopoietic system.
Mangel, Marc; Bonsall, Michael B.
Most actinopterygians replace their teeth continuously throughout life. To address the question of where and how replacement teeth form in actinopterygians, it is advisable to investigate well-chosen representatives within the lineage. The African bichir, Polypterus senegalus, belongs to the earliest diverged group of the actinopterygian lineage with currently living representatives. Its well characterized dentition, together with its phylogenetic position, make this species an attractive model to answer following questions: (1) when and where does the replacement tooth form and how is it connected with the dental organ of the predecessor, and (2) is there any evidence for the presence of epithelial stem cells, hypothesized to play a role in replacement? Serial sections show that one tooth family can contain up to three members, which are all interconnected by dental epithelium. Replacement teeth develop without the presence of a successional dental lamina. We propose that this is the plesiomorphic condition for tooth replacement in actinopterygians. BrdU pulse-chase experiments reveal cells in the outer and middle dental epithelium, proliferating at the time of initiation of a new replacement tooth. It is tempting to assume that these cell layers provide a stem cell niche. The observed absence of label-retaining cells after long chase times (up to 8 weeks) is held against the light of divergent views on cell cycling properties of stem cells. At present, our data do not support, neither reject, the hypothesis on involvement of epithelial stem cells within the process of continuous tooth replacement. J. Exp. Zool. (Mol. Dev. Evol.) 322B: 281-293, 2014. © 2014 Wiley Periodicals, Inc. PMID:24890316
Vandenplas, Sam; De Clercq, Adelbert; Huysseune, Ann
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
Though much has been learned about the process of ovarian follicle maturation through studies of oogenesis in both vertebrate and invertebrate systems, less is known about how follicles form initially. In Drosophila, two somatic follicle stem cells (FSCs) in each ovariole give rise to all polar cells, stalk cells, and main body cells needed to form each follicle. We show that one daughter from each FSC founds most follicles but that cell type specification is independent of cell lineage, in contrast to previous claims of an early polar/stalk lineage restriction. Instead, key intercellular signals begin early and guide cell behavior. An initial Notch signal from germ cells is required for FSC daughters to migrate across the ovariole and on occasion to replace the opposite stem cell. Both anterior and posterior polar cells arise in region 2b at a time when approximately 16 cells surround the cyst. Later, during budding, stalk cells and additional polar cells are specified in a process that frequently transfers posterior follicle cells onto the anterior surface of the next older follicle. These studies provide new insight into the mechanisms that underlie stem cell replacement and follicle formation during Drosophila oogenesis. PMID:19948890
Nystul, Todd; Spradling, Allan
Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14? DC, CD1a?CD14+ DC, and CD1a?CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells.
Haniffa, Muzlifah; Ginhoux, Florent; Wang, Xiao-Nong; Bigley, Venetia; Abel, Michal; Dimmick, Ian; Bullock, Sarah; Grisotto, Marcos; Booth, Trevor; Taub, Peter; Hilkens, Catharien; Merad, Miriam
Stem cells have the ability to both differentiate into other mature cell types and maintain an undifferentiated state by self-renewal. These unique properties form the basis for stem cell use in organ replacement and tissue regeneration in clinical medicine. Currently, embryonic stem cells are the best-studied stem cell type. However alternative stem cells such as induced pluripotent stem cells and
Kehkooi Kee; Renee A. Reijo Pera; Paul J. Turek
The small-sized teleost fish medaka, Oryzias latipes, has as many as 1000 pharyngeal teeth undergoing continuous replacement. In this study, we sought to identify the tooth-forming units and determine its replacement cycles, and further localize odontogenic stem cell niches in the pharyngeal dentition of medaka to gain insights into the mechanisms whereby continuous tooth replacement is maintained. Three-dimensional reconstruction of pharyngeal epithelium and sequential fluorochrome labeling of pharyngeal bones and teeth indicated that the individual functional teeth and their successional teeth were organized in families, each comprising up to five generations of teeth and successional tooth germs, and that the replacement cycle of functional teeth was approximately 4 weeks. BrdU label/chase experiments confirmed the existence of clusters of label-retaining epithelial cells at the posterior end of each tooth family where the expression of pluripotency marker Sox2 was confirmed by in situ hybridization. Label-retaining cells were also identified in the mesoderm immediately adjacent to the posterior end of each tooth family. These data suggest the importance of existence of slow-cycling dental epithelial cells and Sox2 expressions at the posterior end of each tooth family to maintain continuous tooth formation and replacement in the pharyngeal dentition of medaka. PMID:24463193
Abduweli, Dawud; Baba, Otto; Tabata, Makoto J; Higuchi, Kazunori; Mitani, Hiroshi; Takano, Yoshiro
Severe Combined Immunodeficiency (SCID), Systemic Lupus Erythematosus (SLE), and Type I Diabetes share one commonality: these diverse disorders can all be attributed to faulty immune effector cells which are largely caused by genetic mutations that alter hematopoietic cell-intrinsic function. These defective immune cells inherit their genetic deficiencies from hematopoietic stem cells (HSC) as they differentiate. Thus, each of these unique diseases should be theoretically curable through the same strategy: replacement of patients’ HSCs carrying the problematic mutation with normal HSCs from disease-free donors, thereby generating entire new, healthy hematolymphoid systems. Replacement of disease-causing stem cells with healthy ones has been achieved clinically via hematopoietic cell transplantation (HCT) for the last 50 years, as a treatment modality for a variety of cancers and immunodeficiencies with moderate, but increasing success. This has traditionally included transplantation of mixed hematopoietic populations that include HSC and other cells, such as T-cells. This review article explores and delineates the potential expansion of this technique to treat a variety of inherited diseases of immune function, the current barriers in HCT and pure HSC transplantation, as well as the up-and-coming strategies to combat these obstacles.
Czechowicz, Agnieszka; Weissman, Irving
The overarching aim of this study is to assess the feasibility of using periosteal tissue from the femoral neck of arthritic hip joints, usually discarded in the normal course of hip replacement surgery, as an autologous source of stem cells. In addition, the study aims to characterize intrinsic differences between periosteum-derived cell (PDC) populations, isolated via either enzymatic digestion or a migration assay, including their proliferative capacity, surface marker expression, and multipotency, relative to commercially available human bone marrow-derived stromal cells (BMSCs) cultured under identical conditions. Commercial BMSCs and PDCs were characterized in vitro, using a growth assay, flow cytometry, as well as assay of Oil Red O, alizarin red, and Safranin O/Fast Green staining after respective culture in adipo-, osteo-, and chondrogenic media. Based on these outcome measures, PDCs exhibited proliferation rate, morphology, surface receptor expression, and multipotency similar to those of BMSCs. No significant correlation was observed between outcome measures and donor age or diagnosis (osteoarthritis [OA] and rheumatoid arthritis [RA], respectively), a profound finding given recent rheumatological studies indicating that OA and RA share not only common biomarkers and molecular mechanisms but also common pathophysiology, ultimately resulting in the need for joint replacement. Furthermore, PDCs isolated via enzymatic digestion and migration assay showed subtle differences in surface marker expression but otherwise no significant differences in proliferation or multipotency; the observed differences in surface marker expression may indicate potential effects of isolation method on the population of cells isolated and/or the behavior of the respective isolated cell populations. This study demonstrates, for the first time to our knowledge, the feasibility of using arthritic tissue resected during hip replacement as a source of autologous stem cells. In sum, periosteum tissue that is resected with the femoral neck in replacing the hip represents an unprecedented and, to date, unstudied source of stem cells from OA and RA patients. Follow-up studies will determine the degree to which this new, autologous source of stem cells can be banked for future use. PMID:24477075
Chang, Hana; Docheva, Denitsa; Knothe, Ulf R; Knothe Tate, Melissa L
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
Human pluripotent stem cell-derived neural progenitor (hNP) cells are an excellent resource for understanding early neural development and neurodegenerative disorders. Given that many neurodegenerative disorders can be correlated with defects in the mitochondrial genome, optimal utilization of hNP cells requires an ability to manipulate and monitor changes in the mitochondria. Here, we describe a novel approach that uses recombinant human mitochondrial transcription factor A (rhTFAM) protein to transfect and express a pathogenic mitochondrial genome (mtDNA) carrying the G11778A mutation associated with Leber's hereditary optic neuropathy (LHON) disease, into dideoxycytidine (ddC)-treated hNPs. Treatment with ddC reduced endogenous mtDNA and gene expression, without loss of hNP phenotypic markers. Entry of G11778A mtDNA complexed with the rhTFAM was observed in mitochondria of ddC-hNPs. Expression of the pathogenic RNA was confirmed by restriction enzyme analysis of the SfaN1-digested cDNA. On the basis of the expression of neuron-specific class III beta-tubulin, neuronal differentiation occurred. Our results show for the first time that pathogenic mtDNA can be introduced and expressed into hNPs without loss of phenotype or neuronal differentiation potential. This mitochondrial gene replacement technology allows for creation of in vitro stem cell-based models useful for understanding neuronal development and treatment of neurodegenerative disorders. PMID:21918550
Iyer, S; Xiao, E; Alsayegh, K; Eroshenko, N; Riggs, M J; Bennett, J P; Rao, R R
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 and regionally appropriate cell types, and nondisruptive interspersion with host progenitors and their progeny. These human NSCs can be genetically engineered and are capable of expressing foreign transgenes in vivo. Supporting their gene therapy potential, secretory products from NSCs can correct a prototypical genetic metabolic defect in neurons and glia in vitro. The human NSCs can also replace specific deficient neuronal populations. Cryopreservable human NSCs may be propagated by both epigenetic and genetic means that are comparably safe and effective. By analogy to rodent NSCs, these observations may allow the development of NSC transplantation for a range of disorders. PMID:9831031
Flax, J D; Aurora, S; Yang, C; Simonin, C; Wills, A M; Billinghurst, L L; Jendoubi, M; Sidman, R L; Wolfe, J H; Kim, S U; Snyder, E Y
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
Since spermatogonial stem cells (SSCs) are capable of both self-renewal and differentiation to daughter cells for subsequent spermatogenesis, the development of an efficient in vitro culture system is essential for studies related to spermatogenesis. Although the currently available system is serum-free and contains only chemically-defined components, it highly relies upon bovine serum albumin (BSA), a component with batch-to-batch quality variations similar to those of fetal bovine serum. Thus, we searched for an alternative BSA-free culture system that preserved the properties of SSCs. In this study, we utilized Knockout Serum Replacement (KSR) in the SSC culture medium, as a substitute for BSA. The results demonstrated that KSR supported the continuous growth of SSCs in vitro and the SSC activity in vivo without BSA, in a feeder-cell combination with mouse embryonic fibroblasts. The addition of BSA to KSR further facilitated cell cycle progression, whereas a transplantation assay revealed that the addition of BSA did not affect the number of SSCs in vivo. The combination of KSR with BSA also allowed the elimination of GFRA1 and FGF2, and the reduction of the GDNF concentration from 20 ng/ml to 5 ng/ml, while maintaining the growth rate and the expression of SSC markers. Furthermore, KSR was also useful with SSCs from non-DBA/2 strains, such as C57BL/6 and ICR. These results suggested that KSR is an effective substitute for BSA for long-term in vitro cultures of SSCs. Therefore, this method is practical for various studies related to SSCs, including spermatogenesis and germ stem cell biology.
Aoshima, Keisuke; Baba, Ai; Makino, Yoshinori; Okada, Yuki
The development of porcine embryonic stem cell lines (pESC) has received renewed interest given the advances being made in\\u000a the production of immunocompatible transgenic pigs. However, difficulties are evident in the production of pESCs in-vitro.\\u000a This may largely be attributable to differences in porcine pre-implantation development compared to the mouse and human. Expression\\u000a of oct4, nanog and sox2 differs in
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.
Neirinckx, Virginie; Marquet, Alice; Coste, Cecile
Neural differentiation of embryonic and adult stem cells has been reported previously. Several studies have used different proportions of serum or a cocktail of growth and differentiation factors for this purpose. In the present study, we examined neural differentiation of mouse embryonic stem (ES) cells in KoSR-containing media. We also investigated neural differentiation of mouse adipose tissue-derived stem cells (ADSCs) in a medium containing KoSR, a synthetic serum replacement, and compared it with neural differentiation in low-serum condition. Meanwhile, effect of ?-ME on neural differentiation was investigated in both conditions. As revealed by RT-PCR and immunocytochemistry analyses, KoSR-containing medium induced neural differentiation of mouse ES cells. Moreover, under the culture conditions we tested, ADSCs were differentiated to neuron-like cells and expressed some neuronal markers. Low concentration of ?-ME improved neuron-like differentiation of the ADSCs in the 4% FBS-supplemented medium, while addition of ?-ME in KoSR condition decreased neural differentiation. KoSR-containing medium without any additional factor improved generation of neuron-like cells, upregulated the expression of mature neuronal markers and led to the formation of cytoplasmic processes. In summary, our findings are indicating that mouse embryonic and mesenchymal stem cells are capable of neural development in KoSR-containing media. PMID:24355806
Taha, Masoumeh Fakhr; Javeri, Arash; Kheirkhah, Omolbani; Majidizadeh, Tayebeh; Khalatbary, Ali Reza
\\u000a The purpose of hematopoietic stem cell transplantation (HSCT) is to replace diseased, damaged, or absent hematopoietic stem\\u000a cells (HSCs) with healthy HSCs. In general, allogeneic transplants are used when the hematopoietic stem cells are diseased\\u000a (e.g., leukemia), damaged (e.g., sickle cell disease), or absent (e.g., severe immunodeficiency disease). Autologous transplants\\u000a are used to provide stem cell rescue after higher doses
Robbie Norville; Deborah Tomlinson
Cell replacement therapy of neurodegenerative disorders aims to substitute the degenerating cells with new functional neurons. Clinical trails with patients suffering from Parkinson's or Huntington's disease have provided proof-of-principle that neural precursors taken from the developing human brain can survive upon grafting to the diseased brain and provide long-lasting symptomatic relief. However, further development of this type of therapy critically
Cell-based therapies involving tissue engineering represent interesting and potentially important strategies for the treatment of patients with various disorders. In this study, using a detergent-enzymatic method, we prepared an intact three-dimensional scaffold of an extracellular matrix derived from a human cadaver donor trachea, which we repopulated with autologous stem cells and implanted into a 76-year-old patient with tracheal stenosis including the lower part of the larynx. Although the graft provided the patient with an open airway, a week after the surgery, the mucous membrane of the graft was covered by a 1-2 mm thick fungal infection, which was treated with local and systemic antifungal therapy. The airway lumen was postoperatively controlled by fiber endoscopy and found stable and sufficient. However, after 23 days, the patient died due to cardiac arrest but with a patent, open, and stable tracheal transplant and intact anastomoses. Histopathological results of the transplanted tracheal graft during autopsy showed a squamous but not ciliated epithelium, neovascularization, bundles of ?-sma-positive muscle cells, serous glands, and nerve fibers with S-100-positive nerve cells in the submucosa and intact chondrocytes in the cartilage. Our findings suggest that although autologous stem cells-engineered tracheal matrices may represent a tool for clinical tracheal replacement, further preclinical studies are required for generating functional airway grafts and long-term effects of such grafts. PMID:24004248
Berg, Malin; Ejnell, Hasse; Kovács, Anikó; Nayakawde, Nikhil; Patil, Pradeep B; Joshi, Meghnad; Aziz, Luaay; Rĺdberg, Göran; Hajizadeh, Shahin; Olausson, Michael; Sumitran-Holgersson, Suchitra
Gene targeting is a very powerful tool for studying mammalian development and physiology and for creating models of human diseases. In many instances, however, it is desirable to study different modifications of a target gene, but this is limited by the generally low frequency of homologous recombination in mammalian cells. We have developed a novel gene-targeting strategy in mouse embryonic stem cells that is based on the induction of endogenous gap repair processes at a defined location within the genome by induction of a double-strand break (DSB) in the gene to be mutated. This strategy was used to knock in an NH2-ezrin mutant in the villin gene, which encodes an actin-binding protein expressed in the brush border of the intestine and the kidney. To induce the DSB, an I-SceI yeast meganuclease restriction site was first introduced by gene targeting to the villin gene, followed by transient expression of I-SceI. The repair of the ensuing DSB was achieved with high efficiency (6 × 10?6) by a repair shuttle vector sharing only a 2.8-kb region of homology with the villin gene and no negative selection marker. Compared to conventional gene-targeting experiments at the villin locus, this represents a 100-fold stimulation of gene-targeting frequency, notwithstanding a much lower length of homology. This strategy will be very helpful in facilitating the targeted introduction of several types of mutations within a gene of interest.
Cohen-Tannoudji, Michel; Robine, Sylvie; Choulika, Andre; Pinto, Daniel; El Marjou, Fatima; Babinet, Charles; Louvard, Daniel; Jaisser, Frederic
We have analyzed midgut development during the fifth larval instar in the tobacco budworm Heliothis virescens. In prepupae, the midgut formed during larval instars undergoes a complete renewal process. This drastic remodeling of the\\u000a alimentary canal involves the destruction of the old cells by programmed cell-death mechanisms (autophagy and apoptosis).\\u000a Massive proliferation and differentiation of regenerative stem cells take place
Gianluca Tettamanti; Annalisa Grimaldi; Morena Casartelli; Elena Ambrosetti; Benedetta Ponti; Terenzio Congiu; Roberto Ferrarese; Maria Luisa Rivas-Pena; Francesco Pennacchio; Magda de Eguileor
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. In the past few years, major efforts have been made to define more precisely the medium composition in which stem cells grow or differentiate. 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. PMID:20803548
van der Sanden, Boudewijn; Dhobb, Mehdi; Berger, François; Wion, Didier
Pediatric stem cell transplant (SCT) recipients commonly develop acute renal failure (ARF). We report the demographic and survival data of pediatric SCT patients enrolled in the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry. Since 1 January 2001, 51/370 (13.8%) patients entered in the ppCRRT Registry had received a SCT. Median age was 13.63 (0.53-23.52) years. The primary reasons for the initiation of continuous renal replacement therapy (CRRT) were treatment of fluid overload (FO) and electrolyte imbalance (49%), FO only (39%), electrolyte imbalance only (8%) and other reasons (4%). The CRRT modalities included continuous veno-veno hemodialysis (CVVHD), 43%, continuous veno-veno hemofiltration (CVVH), 37% and continuous veno-veno hemodiafiltration (CVVHDF), 20%. Seventy-six percent had multi-organ dysfunction syndrome (MODS), 72% received ventilatory support and the mean FO was 12.41 +/- 3.70%. Forty-five percent of patients survived. Patients receiving convective therapies had better survival rates (59% vs 27%, P < 0.05). Patients requiring ventilatory support had worse survival (35% vs 71%, P < 0.05). Mean airway pressure (Paw) at the end of CRRT was lower in survivors (8.7 +/- 2.94 vs 25.76 +/- 2.03 mmH(2)O, P < 0.05). Development of high mean airway pressure in non-survivors is likely related to non-fluid injury, as it was not prevented by early and aggressive fluid management by CRRT therapy. PMID:18228045
Flores, Francisco X; Brophy, Patrick D; Symons, Jordan M; Fortenberry, James D; Chua, Annabelle N; Alexander, Steven R; Mahan, John D; Bunchman, Timothy E; Blowey, Douglas; Somers, Michael J G; Baum, Michelle; Hackbarth, Richard; Chand, Deepa; McBryde, Kevin; Benfield, Mark; Goldstein, Stuart L
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
\\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
Currently, there is a major need in hematopoietic stem cell (HSC) transplantation to develop reduced-intensity regimens that do not cause DNA damage and associated toxicities and that allow a wider range of patients to receive therapy. Cytokine receptor signals through c-Kit and c-Mpl can modulate HSC quiescence and engraftment, but the intracellular signals and transcription factors that mediate these effects during transplantation have not been defined. Here we show that loss of one allele of signal transducer and activator of transcription 5 (STAT5) in nonablated adult mutant mice permitted engraftment with wild-type HSC. Conditional deletion of STAT5 using Mx1-Cre caused maximal reduction in STAT5 mRNA (> 97%) and rapidly decreased quiescence-associated c-Mpl downstream targets (Tie-2, p57), increased HSC cycling, and gradually reduced survival and depleted the long-term HSC pool. Host deletion of STAT5 was persistent and permitted efficient donor long-term HSC engraftment in primary and secondary hosts in the absence of ablative conditioning. Overall, these studies establish proof of principle for targeting of STAT5 as novel transplantation conditioning and demonstrate, for the first time, that STAT5, a mitogenic factor in most cell types, including hematopoietic progenitors, is a key transcriptional regulator that maintains quiescence of HSC during steady-state hematopoiesis.
Wang, Zhengqi; Li, Geqiang; Tse, William
Background Mucopolysaccharidosis type I is caused by deficiency of ?-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown. Design and Methods We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. Results High titer immune responses were seen in 87.5% (7/8) patients following exposure to ?-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26–137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. Conclusions We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.
Saif, Muhammad Ameer; Bigger, Brian W.; Brookes, Karen E; Mercer, Jean; Tylee, Karen L.; Church, Heather J.; Bonney, Denise K.; Jones, Simon; Wraith, J. Ed; Wynn, Robert F.
Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells
Tannishtha Reya; Sean J. Morrison; Michael F. Clarke; Irving L. Weissman
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
The aim of this retrospective study was to compare the efficacy and safety of standard intravenous ganciclovir (GCV) with low-dose oral valganciclovir (VGC) in preemptive treatment of cytomegalovirus (CMV) infection in patients who received allogeneic stem cell transplantation (ASCT). Fifty-nine adult ASCT patients with asymptomatic 68 CMV reactivations were included. For preemptive CMV treatment, VGC (900 mg/day) in 44 reactivations or GCV (5 mg/kg twice daily during the first week and once daily afterwards) in 24 CMV reactivations were administered for 21 days. Two consecutive negative results for PCR and/or CMV antigenemia were considered as treatment success. All patients with CMV reactivations were on immunosuppressive treatment. While no positivity was identified in any of the patients who received GCV on day 21, low-titer CMV positivity was noted in three of the patients in the VGC group (P = 0·264). In all three patients, VGC was continued at same dose and no positivity result was detected after 2-3 weeks. Low-grade neutropenia and high grade thrombocytopenia were significantly higher in the GCV group than in the VGC group (P = 0·018 and P = 0·04 respectively). Preemptive strategy of oral low-dose VGC appears preferable to the prevention of CMV disease in ASCT. These results require confirmation in prospective larger clinical studies. PMID:24070136
Kaynar, Leylagül; Metan, Gökhan; Gökahmeto?lu, Selma; Kurnaz, Fatih; Mumcuo?lu, Haluk; Öztürk, Ahmet; ??vg?n, Serdar; Pala, Ci?dem; Y?ld?z, Orhan; Eser, Bülent; Ünal, Ali; Çetin, Mustafa
The introduction of small mutations instead of null alleles into the mouse genome has broad applications to the study of protein structure-function relationships and the creation of animal models of human genetic diseases. To test a simple mutational strategy we designed a targeting vector for the mouse proopiomelanocortin (POMC) gene containing a single nucleotide insertion that converts the initial tyrosine codon of beta-endorphin 1-31 to a premature translational termination codon and introduces a unique Hpal endonuclease restriction site. The targeting vector also contains a neo cassette immediately 3' to the last POMC exon and a herpes simplex virus thymidine kinase cassette to allow positive and negative selection. Homologous recombination occurred at a frequency of 1/30 clones of electroporated embryonic stem cells selected in G418 and gancyclovir. 10/11 clones identified initially by a polymerase chain reaction (PCR) strategy had the predicted structure without evidence of concatemer formation by Southern blot analysis. We used a combination of Hpa I digestion of PCR amplified fragments and direct nucleotide sequencing to further confirm that the point mutation was retained in 9/10 clones. The POMC gene was transcriptionally silent in embryonic stem cells and the targeted allele was not activated by the downstream phosphoglycerate kinase-1 promoter that transcribed the neo gene. Under the electroporation conditions used, we have demonstrated that a point mutation can be introduced with high efficiency and precision into the POMC gene using a replacement type vector containing a retained selectable marker without affecting expression of the allele in the embryonic stem cells. A similar strategy may be useful for a wide range of genes. Images
Rubinstein, M; Japon, M A; Low, M J
The shortage of donors for organ transplantation has stimulated research on stem cells as a potential resource for cell-based therapy in all human tissues. Stem cells have been used for regenerative medicine applications in many organ systems, including the genitourinary system. The potential applications for stem cell therapy have, however, been restricted by the ethical issues associated with embryonic stem
Tamer Aboushwareb; Anthony Atala
A subtle mutation that rendered type I collagen resistant to mammalian collagenase has been introduced into the murine Col1a-1 (recently redesignated Cola-1) gene by homologous recombination in embryonic stem (ES) cells. Initially, a "hit and run" procedure was used. Since two steps were required for introducing each mutation and more than one mutation was to be introduced in the same genomic region independently, we have developed a streamlined procedure that involves two sequential replacement-type homologous recombination events. In the first step, an internal deletion was introduced into the Col1a-1 locus along with the positive and negative selectable markers, neo and tk, to mark the region of interest. G418-resistant homologous recombinants were isolated and used in the second step in which the deleted Col1a-1 allele was replaced with a construct containing the desired mutation. Homologous recombinants containing the mutation were identified among the Tk- ES clones after selection with FIAU [1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (called fialuridine)]. Approximately 10% of such clones contained the desired mutation. The double replacement procedure greatly reduces the time and amount of work required to introduce mutations independently into the same or closely linked regions. Once the homologous recombinants derived from the first step are established, the introduction of other mutations into the deleted region becomes a one-step procedure. For X number of introduced mutations, 2X selections are required with the "hit and run" approach, but only X + 1 are required with the double-replacement method. This innovative procedure could be very useful in studies of gene structure and function as well as gene expression and regulation. Images
Wu, H; Liu, X; Jaenisch, R
Stem cells possess two basic characteristics: they are able to renew themselves and to develop into different cell types.\\u000a The link between normal stem cells and tumor cells could be examined in three aspects: what are the differences and similarities\\u000a in the control of self-renewal capacity between stem cells and tumor cells; whether tumor cells arise from stem cells; do
László Kopper; Melinda Hajdú
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
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.
Background and purpose The clinical results of THR may be improved by correct femoral torsion. We evaluated the stem position by postoperative CT examination in 60 patients. Methods 60 patients requiring total hip arthroplasty were prospectively enrolled in this study. Minimally invasive THR was performed (anterior approach) in a lateral decubitus position and each patient underwent a postoperative CT examination. The position of the stem was evaluated by an independent external institution. Results Stem torsion ranged from –19° retrotorsion to 33° antetorsion. Normal antetorsion (i.e 10–15° according to Tönnis) was present in 5 of 60 patients, so the prevalence of abnormal stem antetorsion was 92% (95% CI: 82–97). We found a stem antetorsion outside the range of 0–25° in 21 of 60 hips. Women had a higher mean stem antetorsion (8.0° (SD 11)) than men (1.5° (SD 10)). Interpretation Postoperative stem antetorsion shows a high variability and is gender-related. We suggest precise assessment of stem antetorsion intraoperatively by means of computer navigation, preparing the femur first. In abnormal stem antetorsion, the cup position can be adjusted using a combined anteversion concept; alternatively, modular femoral components or stems with retroverted or anteverted necks (“retrostem”) could be used.
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
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 workshop on Hair Follicle Stem Cells brought together investigators who have used a variety of approaches to try to understand the biology of follicular epithelial stem cells, and the role that these cells play in regulating the hair cycle. One of the main concepts to emerge from this workshop is that follicular epithelial stem cells are multipotent, capable of
Robert M. Lavker; Tung-Tien Sun; Hideo Oshima; Yann Barrandon; Masashi Akiyama; Corinne Ferraris; Genevieve Chevalier; Bertrand Favier; Colin A. B. Jahoda; Danielle Dhouailly; Andrei A. Panteleyev; Angela M. Christiano
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...
Stem cell niches are special microenvironments that maintain stem cells and control their behavior to ensure tissue homeostasis and regeneration throughout life. The liver has a high regenerative capacity that involves stem/progenitor cells when the proliferation of hepatocytes is impaired. In recent years progress has been made in the identification of potential hepatic stem cell niches. There is evidence that hepatic progenitor cells can originate from niches in the canals of Hering; in addition, the space of Disse may also serve as a stem cell niche during fetal hematopoiesis and constitute a niche for stellate cells in adults.
Kordes, Claus; Haussinger, Dieter
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
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
\\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
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
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
Cell transplantation has over the last two decades emerged as a promising approach for restoration of function in neurodegenerative diseases, in particular Parkinson's and Huntington's disease. Clinical trials have so far focused on the use of implants of embryonic mesencephalic tissue containing already fate-committed dopaminergic neuroblasts with the capacity to develop into fully mature dopamine neurons in their new location in the host brain. However, the recent demonstration that immature neural progenitor cells with multipotent properties can be isolated from both the developing and adult CNS and that these cells can be maintained and propagated in culture, has provided a new interesting tool for restorative cell replacement and gene transfer therapies. Embryonic stem cells, obtained from the early stages of embryonic development, and neural stem cells, obtained from the developing brain, may provide renewable sources of cells for therapeutic purposes, and could eventually offer a powerful alternative to primary fetal CNS tissue in clinical transplantation protocols. The purpose of this review is to discuss the prospects of the emerging progenitor cell technology for cell replacement and restorative therapies in neurodegenerative diseases, and consider some of the critical issues that must be solved in order to make progenitor cells useful in studies of brain repair. PMID:11131546
This article is a follow-up to a previous Commentary published in 2011. It updates some of the events mentioned in that Commentary and continues with more interesting and exciting news on stem cell research and the emerging field of Regenerative Medicine. Some of the news includes: 1) the 2012 Nobel Prize for Medicine awarded to John B. Gurdon and Shinya Yamanaka; 2) the cloning of human embryonic stem cells; 3) the continued search for truly pluripotent adult stem cells via in vitro and in vivo protocols; 4) the breakthrough in organ replacements; 5) the global stem cell race; 6) the global stem cell cryo-preservation business; 7) the worldwide stem cell donor registries, and 8) the issue of government regulation on stem cell therapy.
This article is a follow-up to a previous Commentary published in 2011. It updates some of the events mentioned in that Commentary and continues with more interesting and exciting news on stem cell research and the emerging field of Regenerative Medicine. Some of the news includes: 1) the 2012 Nobel Prize for Medicine awarded to John B. Gurdon and Shinya Yamanaka; 2) the cloning of human embryonic stem cells; 3) the continued search for truly pluripotent adult stem cells via in vitro and in vivo protocols; 4) the breakthrough in organ replacements; 5) the global stem cell race; 6) the global stem cell cryo-preservation business; 7) the worldwide stem cell donor registries, and 8) the issue of government regulation on stem cell therapy. PMID:24778557
Since the initial discovery of leukemia stem cells nearly a decade ago, a great deal of cancer research has focused on the\\u000a identification of cancer stem cells (CSCs) in many types of solid tumors, including breast cancer. Through analysis of cell\\u000a surface markers and xenotransplant models, a subpopulation of putative human breast cancer stem cells (BCSCs) that is CD24-negative\\/CD44-positive\\u000a (CD24?\\/CD44+)
Kazuharu Kai; Yoshimi Arima; Toshio Kamiya; Hideyuki Saya
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
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
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 be capable of differentiating into skeletal muscle, brain microglia and astroglia, and hepatocytes. Stem cell lines derived from both embryonic stem and embryonic germ cells (from the embryonic gonadal ridge) are pluripotent and capable of self-renewal for long periods. Therefore embryonic stem and germ cells have been widely investigated for their potential to cure diseases by repairing or replacing damaged cells and tissues. Studies in animal models have shown that transplantation of fetal, embryonic stem, or embryonic germ cells may be able to treat some chronic diseases. In this review, we highlight recent developments in the use of stem cells as therapeutic agents for three such diseases: Diabetes, Parkinson disease, and congestive heart failure. We also discuss the potential use of stem cells as gene therapy delivery cells and the scientific and ethical issues that arise with the use of human stem cells. PMID:12592319
Henningson, Carl T; Stanislaus, Marisha A; Gewirtz, Alan M
Purpose of review To review the latest developments in reproductive tract stem cell biology. Recent findings In 2004, two studies indicated that ovaries contain stem cells which form oocytes in adults and that can be cultured in vitro into mature oocytes. A live birth after orthotopic transplantation of cyropreserved ovarian tissue in a woman whose ovaries were damaged by chemotherapy demonstrates the clinical potential of these cells. In the same year, another study provided novel evidence of endometrial regeneration by stem cells in women who received bone marrow transplants. This finding has potential for the use in treatment of uterine disorders. It also supports a new theory for the cause of endometriosis, which may have its origin in ectopic transdifferentiation of stem cells. Several recent studies have demonstrated that fetal cells enter the maternal circulation and generate microchimerism in the mother. The uterus is a dynamic organ permeable to fetal stem cells, capable of transdifferentiation and an end organ in which bone marrow stem cells may differentiate. Finally stem cell transformation can be an underlying cause of ovarian cancer. Summary Whereas we are just beginning to understand stem cells, the potential implications of stem cells to reproductive biology and medicine are apparent.
Du, Hongling; Taylor, Hugh S.
The mission of the Stem Cell Resources website is "to provide timely, reliable, high-quality and scientifically credible stem cell information for the educational community worldwide." The website is a division of Bioscience Network which publishes online science education materials. On the site, visitors will find a stem cell image library, a multimedia area, and a special section titled "For Educators". In the "For Educators" area, visitors will find links to a primer on stem cells and links to educational resources on stem cells from curriculum to case studies to lesson plans from such trusted sources as the Australian Stem Cell Centre and the National Institutes of Health. Moving on, the "Multimedia" area includes videos that show how embryonic stem cell lines are made, along with other animations and graphics on the topic. Additionally, the site's "SCR Library" area includes the link to the Stem Cell Image Library, which provides dozens of photos of stem cells taken from researchers at the University of Cambridge and other institutions.
The increasing use of the hair follicle as a stem cell paradigm is due in part to the complex interplay between epithelial, dermal and other cell types, each with interesting differentiation potential and prospective therapeutic applications. This review focuses on research into the environmental niche, gene expression profiles and plasticity of hair follicle stem cell populations, where many recent advances
James M. Waters; Gavin D. Richardson; Colin A. B. Jahoda
Stem cells hold significant promise for regeneration of tissue defects and disease-modifying therapies. Although numerous promising stem cell approaches are advancing in clinical trials, intraoperative stem cell therapies offer more immediate hope by integrating an autologous cell source with a well-established surgical intervention in a single procedure. Herein, the major developments in intraoperative stem cell approaches, from in vivo models to clinical studies, are reviewed, and the potential regenerative mechanisms and the roles of different cell populations in the regeneration process are discussed. Although intraoperative stem cell therapies have been shown to be safe and effective for several indications, there are still critical challenges to be tackled prior to adoption into the standard surgical armamentarium.
Coelho, Monica Beato; Cabral, Joaquim M.S.; Karp, Jeffrey M.
Stem cell therapy and translational stem cell research require large-scale supply of stem cells at high purity and viability, thus leading to the development of stem cell separation technologies. This review covers key technologies being applied to stem cell separation, and also highlights exciting new approaches in this field. First, we will cover conventional separation methods that are commercially available and have been widely adapted. These methods include Fluorescence-activated cell sorting (FACS), Magnet-activated cell sorting (MACS), pre-plating, conditioned expansion media, density gradient centrifugation, field flow fractionation (FFF), and dielectrophoresis (DEP). Next, we will introduce emerging novel methods that are currently under development. These methods include improved aqueous two-phase system, systematic evolution of ligands by exponential enrichment (SELEX), and various types of microfluidic platforms. Finally, we will discuss the challenges and directions towards future breakthroughs for stem cell isolation. Advancing stem cell separation techniques will be essential for clinical and research applications of stem cells. PMID:23505616
Zhu, Beili; Murthy, Shashi K
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
Preclinical and clinical research have shown that stem cell therapy could be a promising therapeutic option for many diseases in which current medical treatments do not achieve satisfying results or cure. This article describes stem cells sources and their therapeutic applications in dermatology today.
Ogliari, Karolyn Sassi; Marinowic, Daniel; Brum, Dario Eduardo; Loth, Fabrizio
The isolation of human embryonic stem cells (ESC) in 1998 has created the hope that stem cells will one day be used to regenerate tissues and organs, even though it is obvious that a number of hurdles will need to be overcome for such therapies to become reality. The cloning of “Dolly” in 1997, more than 40 years after the first
The objective of this research was to identify mouse mammary gland stem cells, with the ultimate goal being their isolation. We hypothesized that mammary gland stem cells can be identified by generating transgenic mice using a LEF/TCF-dependent reporter g...
D. J. Sussman
This game uses a modified Uno deck to review concepts related to stem cell research and diabetes. Specifically, it covers material in the "Pulse-Chase Primer," "Pancreatic Beta Cells," and "Microarrays and Stem Cells" activities from the same resource which may or may not be necessary to complete prior to this activity (depending on learner's prior knowledge). Learners accumulate points and answer questions about stem cells, development, and microarrays so that they can be the first to differentiate into a pancreatic beta (Î˛) cell. This activity is recommended for learners studying Biology at the High School (honors, IB and AP) or Undergraduate level.
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
The Echelon Primary femoral stem is an extensively porous coated cylindrical cobalt chrome hip component. A prospective review of 392 Echelon stems revealed excellent survivorship of the stem, with a 99.3% survival rate for aseptic loosening and a 98.3% survival rate for revision for any reason at 8 years. Normalized Western Ontario and McMaster Universities Osteoarthritis Index and short-form health survey outcome scores were significantly improved and subsequently maintained after replacement, with 82% of patients obtaining a good or excellent result at the mean follow-up period. There have been no changes in manufacture or design of the stem during the review period. PMID:19298025
Lewis, Peter M; Olsen, Michael; Schemitsch, Emil H; Waddell, James P
Despite the discovery over 60 years ago by Huggins and Hodges 1 that prostate cancers respond to androgen deprivation therapy, hormone-refractory prostate cancer remains a major clinical challenge. There is now mounting evidence that solid tumours originate from undifferentiated stem cell-like cells coexisting within a heterogeneous tumour mass that drive tumour formation, maintain tumour homeostasis and initiate metastases. This review focuses upon current evidence for prostate cancer stem cells, addressing the identification and properties of both normal and transformed prostate stem cells.
Lang, SH; Frame, FM; Collins, AT
Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.
Guan, Jun-Lin; Simon, Anna Katharina; Prescott, Mark; Menendez, Javier A.; Liu, Fei; Wang, Fen; Wang, Chenran; Wolvetang, Ernst; Vazquez-Martin, Alejandro; Zhang, Jue
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
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
Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson's disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms. PMID:21165156
Nelson, Timothy J; Martinez-Fernandez, Almudena; Yamada, Satsuki; Ikeda, Yasuhiro; Perez-Terzic, Carmen; Terzic, Andre
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
Pluripotent cells, such as embryonic stem cells, are invaluable tools for research and can potentially serve as a source of cell- and tissue-replacement therapy. Rejection after transplantation of cells and tissue derived from embryonic stem cells is a significant obstacle to their clinical use. Recently, human somatic cells have been reprogrammed directly to pluripotency by ectopic expression of four transcription
In-Hyun Park; Paul H Lerou; Rui Zhao; Hongguang Huo; George Q Daley
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
\\u000a \\u000a Just a few short years ago, we still used to think that we were born with a finite number of irreplaceable neurons. However,\\u000a in recent years, there has been increasingly persuasive evidence that suggests that neural stem cell (NSC) maintenance and\\u000a differentiation continue to take place throughout the mammal’s lifetime. Studies suggest that neural stem cells not only persist\\u000a to
Kimberly D. Tran; Allen Ho; Rahul Jandial
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
Allogeneic hematopoietic stem cell transplantation is now an important treatment for numerous diseases. Donation of hematopoietic stem cells, either through bone marrow (BM) harvesting or peripheral blood stem cell (PBSC) collection, is a well-established and generally accepted procedure. The BM is aspirated from the posterior iliac crest under spinal or general anesthesia, and common side effects include fatigue and local pain. PBSC collection requires 4-6 days of G-CSF injections and leukapheresis 1-2 times. Common side effects of these procedures include bone pain, fatigue, and headache. The side effects of BM and PBSC collections are mostly transient and well tolerated. Severe adverse events are uncommon in healthy donors. At present, there is no definitive evidence to show that the stem cell donation increases the risk of marrow failure or cancer development. Nevertheless, all donors must be carefully evaluated and fully informed before donation. Donors must be able to provide informed consent without being coerced or pressured. Donors and graft products must be examined for potential agents to avoid transmitting infections and other diseases that may jeopardize donor's health during stem cell collection or recipient's well being after transplantation. Understanding the potential physical and psychological complications of stem cell donation and factors that may increase risks is very important to ensure that transplantation physicians maintain positive attitude in conducting this benevolent practice. PMID:23420184
Chen, Shu-Huey; Wang, Tso-Fu; Yang, Kuo-Liang
Glioblastomas are highly malignant primary brain tumors with one of the worst survival rates among all human cancers. With a more profound understanding of the cellular and molecular mechanisms of tumor initiation and acquired resistance to conventional radio- and chemotherapy, novel therapeutic targets might be discovered to optimize therapeutic approaches. In this regard, the identification of a small cellular subpopulation, called glioblastoma stem cell or stem-like cells or glioma-initiating cells or brain tumor propagating cells, has gained attention. In this article, we briefly summarize the current state of knowledge about this tumor cell population and discuss future directions for basic and clinical research. PMID:21253762
Tabatabai, Ghazaleh; Weller, Michael
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.
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
Retinal degeneration culminating in photoreceptor loss is the leading cause of untreatable blindness in the developed world. In this review, we consider how photoreceptors might be replaced by transplantation and how stem cells might be optimised for use as donor cells in future clinical strategies for retinal repair. We discuss the current advances in human and animal models of retinal
R E MacLaren; R A Pearson
Microfluidic techniques have been recently developed for cell-based assays. In microfluidic systems, the objective is for these microenvironments to mimic in vivo surroundings. With advantageous characteristics such as optical transparency and the capability for automating protocols, different types of cells can be cultured, screened, and monitored in real time to systematically investigate their morphology and functions under well-controlled microenvironments in response to various stimuli. Recently, the study of stem cells using microfluidic platforms has attracted considerable interest. Even though stem cells have been studied extensively using bench-top systems, an understanding of their behavior in in vivo-like microenvironments which stimulate cell proliferation and differentiation is still lacking. In this paper, recent cell studies using microfluidic systems are first introduced. The various miniature systems for cell culture, sorting and isolation, and stimulation are then systematically reviewed. The main focus of this review is on papers published in recent years studying stem cells by using microfluidic technology. This review aims to provide experts in microfluidics an overview of various microfluidic systems for stem cell research.
Wu, Huei-Wen; Lin, Chun-Che; Lee, Gwo-Bin
Cancer is the main cause of death in advanced countries. It has become progressively clear that cancer cells are distributed in a developmental hierarchy, in which whole cancer tissues originate from cancer stem cells(CSCs). CSCs were first discovered in a case of acute myeloid leukemia. Leukemia stem cells(LSCs)are resistant to conventional chemotherapies because of their dormancy and are therefore the cause of minimal residual disease and relapse. Many investigators are working to develop novel therapeutic strategies for eliminating LSCs. LSC biology is discussed in the first part of this review, and the therapeutic approach to LSC targeting is described in the latter part. PMID:24743272
We have identified a population of primitive cells in normal human post-natal bone marrow that can, at the single cell level, differentiate in many ways and also proliferate extensively. These cells can differentiate in vitro into most mesodermal cell types (for example, bone cells, and others), as well as cells into cells of the nervous system. The finding that stem cells exist in post-natal tissues with previously unknown proliferation and differentiation potential opens up the possibility of using them to treat a host of degenerative, traumatic or congenital diseases.
The cell of origin of cancer has been a strongly debated topic through out the history of cancer research. This review provides a historic framework and a synopsis of how the theories of cancer initiation and progression evolved from early times to the present day. We present the concept of a cancer stem cell, and review for you the literature
JeanMarie Houghton; Alexei Morozov; Iva Smirnova; Timothy C. Wang
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
Visual impairment severely affects the quality of life of patients and their families and is also associated with a deep economic impact. The most common pathologies responsible for visual impairment and legally defined blindness in developed countries include age-related macular degeneration, glaucoma and diabetic retinopathy. These conditions share common pathophysiological features: dysfunction and loss of retinal neurons. To date, two main approaches are being taken to develop putative therapeutic strategies: neuroprotection and cell replacement. Cell replacement is a novel therapeutic approach to restore visual capabilities to the degenerated adult neural retina and represents an emerging field of regenerative neurotherapy. The discovery of a population of proliferative cells in the mammalian retina has raised the possibility of harnessing endogenous retinal stem cells to elicit retinal repair. Furthermore, the development of suitable protocols for the reprogramming of differentiated somatic cells to a pluripotent state further increases the therapeutic potential of stem-cell-based technologies for the treatment of major retinal diseases. Stem-cell transplantation in animal models has been most effectively used for the replacement of photoreceptors, although this therapeutic approach is also being used for inner retinal pathologies. In this review, we discuss recent advances in the development of cell-replacement approaches for the treatment of currently incurable degenerative retinal diseases. PMID:22354517
Schmeer, Christian W; Wohl, Stefanie G; Isenmann, Stefan
ABSTRACT: 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. PMID:22776143
Donnelly, Eleanor M; Lamanna, Jason; Boulis, Nicholas M
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.
Here, the International Society for Stem Cell Research (ISSCR) Clinical Translation Committee introduces a series of articles outlining the current status, opportunities, and challenges surrounding the clinical translation of stem cell therapeutics for specific medical conditions.
Scadden, David; Srivastava, Alok
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
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
\\u000a Tumours are thought to contain a subpopulation of self-renewing stem cells, the so-called cancer stem cells, which maintain the tumour. Moreover, tumours themselves are thought to arise from organ-specific stem cells. In epithelia, transformation of these cells leads to spread of a mutated stem cell clone through the epithelial sheet, leading to the development of a pre-invasive lesion. Barrett’s oesophagus
Nicholas A. Wright
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
Stem cells that have totipotent, pluripotent and multipotent abilities can be divided into two main categories: embryonic stem cells and adult stem cells. Embryonic stem cells originate from the inner cell mass of the blastocyst stage during embryonic development whereas adult stem cells are derived from bone marrow. Stem cells have the ability to differentiate into mature cells or transdifferentiate
Shahrul Hisham; Zainal Ariffin; Rohaya Megat Abdul Wahab; Ismanizan Ismail; Nor Muhammad Mahadi; Zaidah Zainal Ariffin
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
\\u000a Recent results have increased our understanding of normal stem cells and the signalling pathways which regulate them during\\u000a the development of the mammary gland. Tumours in many tissues are now thought to develop from dysregulated stem cells and\\u000a depend on activated stem cell self-renewal pathways such as Notch for their tumourigenic capacity. These cancer stem cells\\u000a are recognised by specific
G. Farnie; R. B. Clarke
\\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
BioEd Online is an "educational resource for educators, students, and parents" from the Baylor College of Medicine. This is an excellent place to find educational materials and current information in the field of biology. The "Hot Topics" section of this site focus on current events and issues in biology that are "receiving national attention." The controversy surrounding embryonic stem cells, and coverage it receives in news and research publications in the United States and around the world definitely warrants a closer look at this issue. This "Hot Topic" compiled by Joseph Marx, PhD, Nancy Moreno, PhD, and Deanne Erdmann, MS, contains a brief discussion of the stem cell debate, and includes references and links for further reading. Related news articles can be found as well. Be sure to check out the related slide sets for both embryonic stem cells and stem cells. These slide shows are an excellent resource to use in the classroom. Just add the slides you wish to use to your tray and then view or download your slide tray for an instant visual resource.
Erdmann, Deanne; Marx, Joseph; Moreno, Nancy
The stem cell/material interface is a complex, dynamic microenvironment in which the cell and the material cooperatively dictate one another's fate: the cell by remodelling its surroundings, and the material through its inherent properties (such as adhesivity, stiffness, nanostructure or degradability). Stem cells in contact with materials are able to sense their properties, integrate cues via signal propagation and ultimately translate parallel signalling information into cell fate decisions. However, discovering the mechanisms by which stem cells respond to inherent material characteristics is challenging because of the highly complex, multicomponent signalling milieu present in the stem cell environment. In this Review, we discuss recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions, and overview a subset of the operative signal transduction mechanisms that have begun to emerge. Further developments in stem cell engineering and mechanotransduction are poised to have substantial implications for stem cell biology and regenerative medicine.
Murphy, William L.; McDevitt, Todd C.; Engler, Adam J.
The stem cell/material interface is a complex, dynamic microenvironment in which the cell and the material cooperatively dictate one another's fate: the cell by remodelling its surroundings, and the material through its inherent properties (such as adhesivity, stiffness, nanostructure or degradability). Stem cells in contact with materials are able to sense their properties, integrate cues via signal propagation and ultimately translate parallel signalling information into cell fate decisions. However, discovering the mechanisms by which stem cells respond to inherent material characteristics is challenging because of the highly complex, multicomponent signalling milieu present in the stem cell environment. In this Review, we discuss recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions, and overview a subset of the operative signal transduction mechanisms that have begun to emerge. Further developments in stem cell engineering and mechanotransduction are poised to have substantial implications for stem cell biology and regenerative medicine. PMID:24845994
Murphy, William L; McDevitt, Todd C; Engler, Adam J
Abstract The amnion membrane is developed from embryo-derived cells, and amniotic cells have been shown to exhibit multidifferentiation potential. These cells represent a desirable source for stem cells for a variety of reasons. However, to date very few molecular analyses of amnion-derived cells have been reported, and efficient markers for isolating the stem cells remain unclear. This paper assesses the characterization of amnion-derived cells as stem cells by examining stemness marker expressions for amnion-derived epithelial cells and mesenchymal cells by flow cytometry, immunocytochemistry, and quantitative PCR. Flow cytometry revealed that amnion epithelial cells expressed CD133, CD 271, and TRA-1-60, whereas mecenchymal cells expressed CD44, CD73, CD90, and CD105. Immunohistochemistry showed that both cells expressed the stemness markers Oct3/4, Sox2, Klf4, and SSEA4. Stemness genes' expression in amnion epithelial cells, mesenchymal cells, fibroblast, bone marrow-derived mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) was compared by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Amnion-derived epithelial cells and mesenchymal cells expressed Oct3/4, Nanog, and Klf4 more than bone marrow-derived MSCs. The sorted TRA1-60-positive cells expressed Oct3/4, Nanog, and Klf4 more than unsorted cells or TRA1-60-negative cells. TRA1-60 can be a marker for isolating amnion epithelial stem cells. PMID:25068631
Koike, Chika; Zhou, Kaixuan; Takeda, Yuji; Fathy, Moustafa; Okabe, Motonori; Yoshida, Toshiko; Nakamura, Yukio; Kato, Yukio; Nikaido, Toshio
In this activity, learners use microarray technology to determine which genes are turned on and off at various points in the differentiation of pluripotent stem cells on their way to becoming pancreatic Î˛ cells. An introductory PowerPoint, reading, video clip and an animation provide learners with background information needed to interpret the results of a paper microarray simulation. Learners will position cDNA strips on mini-microarrays to discover which genes are expressing, to what degree they are expressing, and which are not. They use these findings to trace the differentiation of embryonic stem cells that give rise to pancreatic Î˛ cells and other cell types. The role of growth factors and proximity of other cell types is central to learners understanding how researchers may direct the ultimate fate of stem cells. The value of this in treating diabetes is also discussed. This activity is recommended for learners studying Biology at the High School (honors, IB and AP) or Undergraduate level.
The concept that stem cells are controlled by particular microenvironments known as 'niches' has been widely invoked. But niches have remained largely a theoretical construct because of the difficulty of identifying and manipulating individual stem cells and their surroundings. Technical advances now make it possible to characterize small zones that maintain and control stem cell activity in several organs, including
Allan Spradling; Daniela Drummond-Barbosa; Toshie Kai
The mucosal lining (endometrium) of the human uterus undergoes cyclical processes of regeneration, differentiation and shedding as part of the menstrual cycle. Endometrial regeneration also follows parturition, almost complete resection and in post-menopausal women taking estrogen replacement therapy. In non-menstruating species, there are cycles of endometrial growth and apoptosis rather than physical shedding. The concept that endometrial stem\\/ progenitor cells
C. E. Gargett
Duchenne muscular dystrophy (DMD) is a lethal muscle disease for which an effective treatment is urgently needed. The use of stem cells to produce normal muscle cells to replace the missing dystrophin protein has attracted much attention. Claims of success using stem cell treatment in animal models of human muscle diseases require careful evaluation and are not necessarily easily extrapolated
Miranda D. Grounds; Kay E. Davies
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
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
\\u000a The hypothesis that tumor initiation and growth are driven by a subpopulation of malignant cells, that is, cancer stem cells\\u000a (CSCs), has received considerable attention. The CSC concept predicts that the design of novel therapies that ablate CSCs\\u000a or target CSC-specific protumorigenic signaling pathways might result in more durable therapeutic responses in cancer patients\\u000a than those achieved by therapeutic approaches
Tobias Schatton; Markus H. Frank
Wong and Reiter have explored the possibility that hair follicle stem cells can give rise to basal cell carcinoma (BCC). They\\u000a expressed in mice an inducible human BCC-derived oncogenic allele of Smoothened, SmoM2, under the control of either the cytokeratin 14 (K14) or cytokeratin 15 (K15) promoter. Smoothened encodes a G-protein-coupled receptor protein in the hedgehog pathway, the misregulation of
Background The epidermis is an important protective barrier that is essential for maintenance of life. Maintaining this barrier requires continuous cell proliferation and differentiation. Moreover, these processes must be balanced to produce a normal epidermis. The stem cells of the epidermis reside in specific locations in the basal epidermis, hair follicle and sebaceous glands and these cells are responsible for replenishment of this tissue. Scope of review A great deal of effort has gone into identifying protein epitopes that mark stem cells, in identifying stem cell niche locations, and in understanding how stem cell populations are related. We discuss these studies as they apply to understanding normal epidermal homeostasis and skin cancer. Major conclusions An assortment of stem cell markers have been identified that permit assignment of stem cells to specific regions of the epidermis, and progress has been made in understanding the role of these cells in normal epidermal homeostasis and in conditions of tissue stress. A key finding is the multiple stem cell populations exist in epidermis that give rise to different structures, and that multiple stem cell types may contribute to repair in damaged epidermis. General significance Understanding epidermal stem cell biology is likely to lead to important therapies for treating skin diseases and cancer, and will also contribute to our understanding of stem cells in other systems. This article is part of a Special Issue entitled Biochemistry of Stem Cells.
Eckert, Richard L.; Adhikary, Gautam; Balasubramanian, Sivaprakasam; Rorke, Ellen A.; Vemuri, Mohan C.; Boucher, Shayne E.; Bickenbach, Jackie R.; Kerr, Candace
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
Stem cells have the ability to differentiate into specific cell types. The two defining characteristics of a stem cell are perpetual self-renewal and the ability to differentiate into a specialized adult cell type. There are two major classes of stem cells: pluripotent that can become any cell in the adult body, and multipotent that 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.
Biehl, Jesse K.; Russell, Brenda
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 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
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. PMID:17709737
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
Mesenchymal stem cells (MSCs) exist in most adult tissues and have been located near or within blood vessels. Although “perivascular” has been commonly used to describe such locations, increasing evidence points at the vessel wall as the exact location. Thus, “vascular stem cells (VSCs)” is recommended as a more accurate term for MSCs. Furthermore, 2 cell populations, namely pericytes and adventitial progenitor cells (APCs), are the likely VSCs. The pericyte evidence relies on the so-called pericyte-specific markers, but none of these markers is pericyte specific. In addition, pericytes appear to be too functionally diverse and sophisticated to have a large differentiation capacity. On the other hand, APCs are more naďve functionally and, therefore, more akin to being VSCs. In vitro, these cells spontaneously differentiate into pericytes, and can be induced to differentiate into vascular cells (endothelial and smooth muscle cells) and mesenchymal cells (eg, bone, cartilage, and fat). In vivo, indirect evidence also points to their ability to differentiate into mesenchymal cells of their native tissue (eg, fat). Moreover, they possess a large paracrine capacity and, therefore, can help maintain tissue homeostasis by encouraging the replication and differentiation of mesenchymal cells locally. These proposed in vivo functions are areas of interest for future research on VSCs.
Lue, Tom F.
The capacity of hepatocytes and cholangiocytes to contribute to their own maintenance has long been recognized. More recently, studies have indicated the presence of both intra-hepatic and extra-hepatic stem/progenitor cell populations. The intraorgan compartment probably derives primarily from the biliary tree, most particularly the most proximal branches, i.e. the canals of Hering and smallest ductules. The extra-organ compartment is at least in part derived from diverse populations of cells from the bone marrow. These three tiers of liver cell regeneration serve to maintain the normal organ and to regenerate damaged parenchyma in response to a variety of insults. The nature and extent of the insult determines the balance between these stem/progenitor compartments. PMID:19002950
Theise, Neil D
It has been hypothesized that cancer stem cells result from the initiation of normal tissue stem cells by mutagens. These\\u000a cells give rise to a population of growth and differentiation dysregulated transient amplifying cells that represent the bulk\\u000a of the tumor. Fifty years of research has provided a relatively large knowledge base on adult liver stem cells termed “oval\\u000a cells”
Thomas Shupe; Bryon E. Petersen
Within the bone marrow stroma are multipotential cells which are capable of differentiation into a number of mesenchymal cell lineages. These cells, termed mesenchymal stem cells, have recently been identified and characterized in humans. Many studies indicate that the bone marrow stroma is damaged following bone marrow transplantation. Since the marrow stroma is critical for the maintenance of hematopoiesis, its ability to support hematopoiesis following stem cell transplantation may be impaired. Animal models suggest that the transplantation of healthy stromal elements, including mesenchymal stem cells, may enhance the ability of the bone marrow microenvironment to support hematopoiesis after stem cell transplantation. Here the authors review recent data that suggest that mesenchymal stem cells may possess therapeutic value not only for the repair of damaged mesenchymal tissues following hematopoietic stem cell transplantation, but also as potential vectors for the delivery of corrective genes. PMID:11055509
Devine, S M; Hoffman, R
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
Cardiomyocytes are terminally differentiated cells with limited regenerative capacity in the adult heart, making cell replacement therapy an attractive option to repair injured hearts. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are pluripotent and capable of infinite expansion in vitro, implicating them as ideal cell types for cell replacement therapy. During the past several years, significant advances in iPS cell generation technology, cardiac differentiation, and cell purification protocols were achieved for the development of stem cell-based heart therapies. The discovery of iPS cells has also sparked the novel idea of direct conversion of mature cell types into another cell type without passing through a pluripotent stem cell state. Functional cardiomyocytes could therefore be directly reprogrammed from differentiated somatic cells by transduction of the three cardiac transcription factors, Gata4, Mef2c, and Tbx5. Herein, we review the recent research achievements and discuss future challenges in stem cell-based cardiac generation and direct cardiac reprogramming technology for heart regeneration. PMID:22652883
Ieda, Masaki; Fukuda, Keiichi
Retinal degeneration represents a huge burden of blinding disease, and currently there are no effective treatments that reverse the most common causes of neural retinal degeneration. Stem cell biology has the potential to significantly ease this burden, not only through the development of disease models of retinal degeneration but also in the manufacture of a replacement for the neural retinal tissue. This review summarizes the major advancements in the last decade in the field of neural retinal regeneration with an emphasis on the differentiation of embryonic and induced pluripotent stem cells into cells with retinal and specifically photoreceptor characteristics. PMID:24732764
Ramsden, Conor M; Powner, Michael B; Carr, Amanda-Jayne F; Smart, Matthew J K; da Cruz, Lyndon; Coffey, Peter J
In the past few years, progress being made in stem cell studies has incontestably led to the hope of developing cell replacement based therapy for diseases deficient in effective treatment by conventional ways. The induced pluripotent stem cells (iPSCs) are of great interest of cell therapy research because of their unrestricted self-renewal and differentiation potentials. Proof of principle studies have successfully demonstrated that iPSCs technology would substantially benefit clinical studies in various areas, including neurological disorders, hematologic diseases, cardiac diseases, liver diseases and etc. On top of this, latest advances of gene editing technologies have vigorously endorsed the possibility of obtaining disease-free autologous cells from patient specific iPSCs. Here in this review, we summarize current progress of stem cell therapy research with special enthusiasm in iPSCs studies. In addition, we compare current gene editing technologies and discuss their potential implications in clinic application in the future.
Xu, Xiu-ling; Yi, Fei; Pan, Hui-ze; Duan, Shun-lei; Ding, Zhi-chao; Yuan, Guo-hong; Qu, Jing; Zhang, Hai-chen; Liu, Guang-hui
Any clinician dreams to obtain the regeneration of the destroyed organ for his patient. In the human being, the regeneration of complex structures is not possible, except the liver and the bone marrow, which can be regenerated because of the presence of adult stem cells in these tissues. The stem cells have two principal properties: they ensure their self-renewal and they have the ability to differentiate into several cellular types. Using specific markers allowing the identification of the stem cells in bone marrow, stem cells were observed in dental pulp tissues. Although the origin, the identification, and the localization of these stem cells of dental pulp remain under consideration, the optimism in research on stem cells permits to believe that the knowledge on dental stem cells will lead to their use in therapeutics. PMID:17720580
Renard, Emmanuelle; Lopez-Cazaux, Séréna; Guicheux, Jérome; Weiss, Pierre; Laboux, Olivier; Alliot-Licht, Brigitte
\\u000a The broad definition of a stem cell is a population of cells that has the ability to self-renew and to differentiate into\\u000a one or more types of specialized terminally differentiated cells. It has become evident that stem cells persist in and can\\u000a be isolated from many organs postnatally. Stem cells isolated from various sources have been demonstrated to vary in
Cynthia B. Ripoll; Bruce A. Bunnell
Huntington's disease (HD) is a progressive neurodegenerative disease that is marked by choreic movements and a decline in cognitive abilities. Adult stem cells such as adult neural stem cells (ANSCs) and mesenchymal stem cells (MSCs) exhibit the ability to differentiate into neural lineages representing an attractive source for cell replacement therapy in neurological disorders, such as HD. ANSCs have been
J. ROSSIGNOL; K. K. DAVIS; S. C. CLERC; S. A. LOWRANCE; J. J. MATCHYNSKI; M. C. BOMBARD; K. D. FINK; K. RABER; S. VON HÖRSTEN; L. LESCAUDRON; G. L. DUNBAR
One of the most exciting developments in the biological sciences in the past decade has been the discovery and characterization of human embryonic stem cells (ESCs). The interest to transplanters is the potential applications of stem cells in regenerative medicine (RM), which may involve tissue engineering, genetic engineering, and other techniques to repair, replace, or regenerate failing tissues and organs.
A. S. Daar; A. Bhatt; E. Court; P. A. Singer
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
Adult stem cells have been identified in the highly regenerative human endometrium on the basis of their functional attributes. They can reconstruct endometrial tissue in vivo suggesting their possible use in treating disorders associated with inadequate endometrium. The identification of specific markers for endometrial mesenchymal stem cells and candidate markers for epithelial progenitor cells enables the potential use of endometrial stem/progenitor cells in reconstructing endometrial tissue in Asherman syndrome and intrauterine adhesions. PMID:22657248
Gargett, Caroline E; Ye, Louie
Recent landmark experiments have shown that transient overexpression of a small number of transcription factors can reprogram differentiated cells into induced pluripotent stem (iPS) cells that resemble embryonic stem (ES) cells. These iPS cells hold great promise for medicine because they have the potential to generate patient-specific cell types for cell replacement therapy and produce in vitro models of disease,
Michael J. Boland; Jennifer L. Hazen; Kristopher L. Nazor; Alberto R. Rodriguez; Wesley Gifford; Greg Martin; Sergey Kupriyanov; Kristin K. Baldwin
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
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 (EP) treatment and increased breast cancer risk, and I explored the hypothesis that women who develop breast cancer while on EP had occult, undiagnosed disease before they started therapy.
Kathryn B. Horwitz
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
Despite the multitude of intensive research, the exact pathophysiological mechanisms underlying movement disorders including Parkinson's disease, multiple system atrophy and Huntington's disease remain more or less elusive. Treatments to halt these disease progressions are currently unavailable. With the recent induced pluripotent stem cells breakthrough and accomplishment, stem cell research, as the vast majority of scientists agree, holds great promise for relieving and treating debilitating movement disorders. As stem cells are the precursors of all cells in the human body, an understanding of the molecular mechanisms that govern how they develop and work would provide us many fundamental insights into human biology of health and disease. Moreover, stem-cell-derived neurons may be a renewable source of replacement cells for damaged neurons in movement disorders. While stem cells show potential for regenerative medicine, their use as tools for research and drug testing is thought to have more immediate impact. The use of stem-cell-based drug screening technology could be a big boost in drug discovery for these movement disorders. Particular attention should also be given to the involvement of neural stem cells in adult neurogenesis so as to encourage its development as a therapeutic option. PMID:24262163
Mochizuki, Hideki; Choong, Chi-Jing; Yasuda, Toru
Research using human embryonic stem cell (hESC) lines has expanded dramatically because of two attractive capacity; self-renewal and differentiation into almost all cell types. For therapeutic purposes, many researchers are trying to establish methods for maintaining pluripotency in defined xeno-free conditions and scalable culture systems. Banking of hESC lines is important for the wide spread of personalized cell therapy and transplantation. We introduced the ongoing clinical trials using hESC-derived cells in patients with subacute spinal cord injury and Stargardt's macular dystrophy. We also discussed opportunities and an example for the use of hESC in drug discovery. Finally, we introduced transgenic hESC as a disease model. PMID:22242306
Kadota, Shin; Aiba, Kazuhiro; Nakatsuji, Norio
1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense e
Ostenfeld, T; Svendsen, C N
In the face of extraordinary advances in the prevention, diagnosis, and treatment of human diseases, the inability of most tissues and organs to repair and regenerate after damage is a problem that needs to be solved. Stem cell research is being pursued in the hope of achieving major medical breakthroughs. Scientists are striving to create therapies that rebuild or replace damaged cells with tissues grown from stem cells that will offer hope to people suffering from various ailments. Regeneration of damaged periodontal tissue, bone, pulp, and dentin is a problem that dentists face today. Stem cells present in dental pulp, periodontal ligament, and alveolar bone marrow have the potential to repair and regenerate teeth and periodontal structures. These stem cells can be harvested from dental pulp, periodontal ligament, and/or alveolar bone marrow; expanded; embedded in an appropriate scaffold; and transplanted back into a defect to regenerate bone and tooth structures. These cells have the potential to regenerate dentin, periodontal ligament, and cementum and can also be used to restore bone defects. The kind of scaffold, the source of cells, the type of in vitro culturing, and the type of surgical procedure to be used all require careful consideration. The endeavor is clearly multidisciplinary in nature, and the practicing dental surgeon has a critical role in it. Playing this role in the most effective way requires awareness of the huge potential associated with the use of stem cells in a clinical setting, as well as a proper understanding of the related problems. PMID:24683584
Mathur, Shivani; Chopra, Rahul; Pandit, I K; Srivastava, Nikhil; Gugnani, Neeraj
Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington' disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease. PMID:18368305
Hou, LingLing; Hong, Tao
Embryonic stem cells represent an attractive source of cardiomyocytes for cell-replacement therapies. However, before embryonic stem cells can be successfully used for the treatment of cardiac diseases, the precise molecular mechanisms that underlie their cardiogenic differentiation must be identified. A network of intrinsic and extrinsic factors regulates embryonic stem cell self-renewal and differentiation into a variety of different cell lineages.
Mohamed Nemir; Adrien Croquelois; Thierry Pedrazzini; Freddy Radtke
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.
Access to the article is free, however registration and sign-in are required. Stem cells have the ability to self-renew and to differentiate into a variety of different cell types. However, it is not clear what determines the path taken by any particular stem cell. Discussing recent work with stem cells from the fruit fly testis (Yamashita et al.), Wallenfang and Matunis explain in their Perspective that, at least in the case of these stem cells, the trick is the asymmetric arrangement of the mitotic spindle during cell division. This asymmetric arrangement ensures that as the stem cell divides, one daughter cell remains in the environmental niche of the testis and continues to self-renew, whereas the other daughter cell is edged out of the niche and begins to differentiate.
Matthew R. Wallenfang (University of Pennsylvania;Department of Cell and Developmental Biology); Erika Matunis (The Johns Hopkins Medical Institutions;Department of Cell Biology)
Stem cells hold remarkable promise for applications in disease modeling, cancer therapy and regenerative medicine. Despite the significant progress made during the last decade, designing materials to control stem cell fate remains challenging. As an alternative, materials microarray technology has received great attention because it allows for high throughput materials synthesis and screening at a reasonable cost. Here, we discuss recent developments in materials microarray technology and their applications in stem cell engineering. Future opportunities in the field will also be reviewed.
\\u000a Accumulated data suggest that the unique function of stem cells to self-renew is under the strong control of a sensor system\\u000a detecting potential threats to genomic integrity. Reactive oxygen species, the most significant mutagens in stem cells, when\\u000a elevated, activate the protective mechanisms blocking self-renewal and at the same time serve as a signal stimulating stem\\u000a cell differentiation. Based on
Irene Riz; Robert G. Hawley
The in vitro generation of hematopoietic stem cells (HSCs) and mature hematopoietic cells from hemangioblast derived from embryonic stem (ES) or induced pluripotent stem (iPS) cells promises to provide an alternative source of cells that could replace total bone marrow cells or HSC-enriched fractions. This mini-review deals with innovation related to hemangioblast-based methods for blood cells production as disclosed in recent patent literature and current barriers to clinical translation are discussed. PMID:23017150
Forte, Laura; Berardi, Anna C
Neuronal degenerations in the retina are leading causes of blindness. Like most other areas of the CNS, the neurons of the mammalian retina are not replaced following degeneration. However, in non-mammalian vertebrates, endogenous repair processes restore neurons very efficiently, even after complete loss of the retina. We describe the phenomenon of retinal regeneration in non-mammalian vertebrates and attempts made in recent years to stimulate similar regenerative processes in the mammalian retina. In addition, we review the various strategies employed to replace lost neurons in the retina and the recent use of stem cell technologies to address problems of retinal repair.
Lamba, Deepak; Karl, Mike; Reh, Thomas
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: firstname.lastname@example.org
It is a general concern that the success of regenerative medicine-based applications is based on the ability to recapitulate the molecular events that allow stem cells to repair the damaged tissue/organ. To this end biomaterials are designed to display properties that, in a precise and physiological-like fashion, could drive stem cell fate both in vitro and in vivo. The rationale is that stem cells are highly sensitive to forces and that they may convert mechanical stimuli into a chemical response. In this review, we describe novelties on stem cells and biomaterials interactions with more focus on the implication of the mechanical stimulation named mechanotransduction.
D'Angelo, Francesco; Tiribuzi, Roberto; Armentano, Ilaria; Kenny, Jose Maria; Martino, Sabata; Orlacchio, Aldo
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
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
Human embryonic stem cells (hESCs) have an unlimited capacity to proliferate by a self-renewal process and can be differentiated in the three germ layers, opening doors to new clinical therapies to replace missing or damaged cells. The number of research groups and projects using human stem cells has increased largely in the last 5 yr. The creation of stem cell banks is another important step to support the advance of research in this field. Banks must be operated within the strict regulatory famework of good manufacturing practices and good laboratory practices that assure the highest quality standards and must implement a quality system that complies with international quality systems standards. It may also be appropriate to aim at an accreditation in order to assure correct laboratory practices at all times. Stem cell banks should receive the lines previously derived by other groups and hESCs should be provided for groups that justify their use in a research project previously approved by an ethical committee. The assays generally accepted as typical of hESCs together with the microbiological analysis should be performed in order to assure a consistent, reliable, and safe line for the researchers. In this article, the Andalusian Stem Cell Bank proposes a model of a stem cell banking process in order to create a flow diagram of hESC lines and, following the international initiatives in stem cells research, to achieve the full characterization of cells and a standardization of protocols that would simplify the hESCs culture. PMID:17237550
Nieto, A; Cobo, F; Barroso-Deljesús, A; Barnie, A H; Catalina, P; Cabrera, C M; Cortes, J L; Montes, R M; Concha, A
Retinal degeneration such as age-related macular degeneration and other inherited forms, such as Stargardt's disease and retinitis pigmentosa, and optic neuropathies including glaucoma and ischemic optic neuropathy are major causes of vision loss and blindness worldwide. Damage to retinal pigment epithelial cells and photoreceptors in the former, and to retinal ganglion cell axons in the optic nerve and their cell bodies in the retina in the latter diseases lead to the eventual death of these retinal cells, and in humans there is no endogenous replacement or repair. Cell replacement therapies provide 1 avenue to restore function in these diseases, particularly in the case of retinal repair, although there are considerable issues to overcome, including the differentiation and integration of the transplanted cells. What stem cell sources could be used for such therapies? One promising source is induced pluripotent stem cells (iPSCs), which could be drawn from an individual patient needing therapy, or generated and banked from select donors. We review developing research in the use of iPSCs for retinal cell replacement therapy. PMID:24291154
Al-Shamekh, Shomoukh; Goldberg, Jeffrey L
Stem cell maintenance depends on their surrounding microenvironment, and aberrancies in the environment have been associated with tumorigenesis. However, it remains to be elucidated whether an environmental aberrancy can act as a carcinogenic stress for cellular transformation of differentiating stem cells into cancer stem cells. Here, utilizing mouse embryonic stem cells as a model, it was illustrated that environmental aberrancy during differentiation leads to the emergence of pluripotent cells showing cancerous characteristics. Analogous to precancerous stages, DNA lesions were spontaneously accumulated during embryonic stem cell differentiation under aberrational environments, which activates barrier responses such as senescence and apoptosis. However, overwhelming such barrier responses, piled-up spheres were subsequently induced from the previously senescent cells. The sphere cells exhibit aneuploidy and dysfunction of the Arf-p53 module as well as enhanced tumorigenicity and a strong self-renewal capacity, suggesting development of cancerous stem cells. Our current study suggests that stem cells differentiating in an aberrational environment are at risk of cellular transformation into malignant counterparts.
Fujimori, Hiroaki; Shikanai, Mima; Teraoka, Hirobumi; Masutani, Mitsuko; Yoshioka, Ken-ichi
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
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). PMID:21607113
Ramirez, Jean-Marie; Bai, Qiang; Dijon-Grinand, Marilyne; Assou, Said; Gerbal-Chaloin, Sabine; Hamamah, Samir; De Vos, John
Embryonic stem (ES) cells hold great promise for treating degenerative diseases, including diabetes, Parkinson's, Alzheimer's, neural degeneration, and cardiomyopathies. This research is controversial to some because producing ES cells requires destroying embryos, which generally means human embryos. However, some of the surplus human embryos available from in vitro fertilization (IVF) clinics may have a high rate of genetic errors and therefore would be unsuitable for ES cell research. Although gross chromosome errors can readily be detected in ES cells, other anomalies such as mitochondrial DNA defects may have gone unrecognized. An insurmountable problem is that there are no human ES cells derived from in vivo-produced embryos to provide normal comparative data. In contrast, some monkey ES cell lines have been produced using in vivo-generated, normal embryos obtained from fertile animals; these can represent a "gold standard" for primate ES cells. In this review, we argue a need for strong research programs using rhesus monkey ES cells, conducted in parallel with studies on human ES and adult stem cells, to derive the maximum information about the biology of normal stem cells and to produce technical protocols for their directed differentiation into safe and functional replacement cells, tissues, and organs. In contrast, ES cell research using only human cell lines is likely to be incomplete, which could hinder research progress, and delay or diminish the effective application of ES cell technology to the treatment of human diseases. PMID:15971982
Bavister, Barry D; Wolf, Don P; Brenner, Carol A
Recently, there has been a growing interest to apply 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 proteins 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 cell 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.
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.
\\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
Adult tissues undergo continuous cell turnover in response to stress, damage, or physiological demand. New differentiated cells are generated from dedicated or facultative stem cells or from self-renewing differentiated cells. Here we describe a different stem cell strategy for tissue maintenance, distinct from that observed for dedicated or facultative stem cells. We report the presence of nestin-expressing adult stem cells
Anatoli S. Gleiberman; Tatyana Michurina; Juan M. Encinas; Jose L. Roig; Peter Krasnov; Francesca Balordi; Gord Fishell; Michael G. Rosenfeld; Grigori Enikolopov
\\u000a Transplantation of hemapoietic stem cell (HSCs) is an accepted treatment for hematological diseases such as severe aplastic\\u000a anemia and most leukemias. In This setting, the HSC are used tom replace the diseased or damaged bone marrow (BM) (13).More recently, HSC have been used to restore BM function following treatment with high dose chemotheraphy and\\/or radiation\\u000a in patients with lymphomas and
Patricia L. Kotula; Ellen M. Areman; Ronald A. Sacher
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
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
Stem cells that can be derived from fetal membranes represent an exciting field of research that bears tremendous potential for developmental biology and regenerative medicine. In this report we summarize contributions to a workshop in which newest insights into the characteristics, subtypes and molecular determinants of stem cells from trophoblast and endometrial tissues were presented.
M. Hemberger; W. Yang; D. Natale; Thomas L. Brown; C. Dunk; C. E. Gargett; S. Tanaka
Recent years have seen much excitement over the possibility that adult mammalian stem cells may be capable of differentiating across tissue lineage boundaries, and as such may represent novel, accessible, and very versatile effectors of therapeutic tissue regeneration. Yet studies proposing such “plasticity” of adult somatic stem cells remain controversial, and in general, existing evidence suggests that in vivo such
Amy J Wagers; Irving L Weissman
While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organ-specific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts. PMID:19085991
Alison, M R; Islam, S
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.
Stem cells have the ability both to differentiate into numerous tissues and to self-renew. Because of these unique properties,\\u000a stem cells are promising candidates for use in regenerative medicine. Among stem cell types, embryonic stem (ES) cells have\\u000a been the most studied; however, alternatives such as induced pluripotent stem cells or other adult stem cells are now being\\u000a established. In
Hideyuki Kobayashi; Koichi Nakajima
This lecture series, from the Howard Hughes Medical Institute Biointeractive project, features five lectures: "Understanding Embryonic Stem Cells," "Adult Stem Cells and Regeneration," "Coaxing Embryonic Stem Cells," "Stem Cells and the End of Aging," and "Stem Cell Research: Policies and Ethics." Each lecture, available in Flash and RealPlayer format, contains interviews, animations, and narratives to help students understand more about stem cells, their applications, and further research.
Purpose of review Regenerative medicine offers the exciting potential of developing alternatives to total joint replacement for treating osteoarthritis (OA). In this article, we highlight recent work that addresses key challenges of stem cell-based therapies for OA and provide examples of innovative ways in which stem cells can aid in the treatment of OA. Recent findings Significant progress has been made in understanding the challenges to successful stem cell therapy, such as the effects of age or disease on stem cell properties, altered stem cell function due to an inflammatory joint environment, and phenotypic instability in vivo. Novel scaffold designs have been shown to enhance the mechanical properties of tissue-engineered cartilage and have also improved the integration of newly formed tissue within the joint. Emerging strategies such as injecting stem cells directly into the joint, manipulating endogenous stem cells to enhance regenerative capacity, and utilizing stem cells for drug discovery have expanded the potential uses of stem cells in treating OA. Summary A number of recent studies have greatly advanced the development and pre-clinical evaluation of potential stem cell-based treatments for OA through novel approaches focused on cell therapy, tissue engineering, and drug discovery.
Diekman, Brian O.; Guilak, Farshid
Osteoporosis is a debilitating disease that affects millions of people worldwide. Current osteoporosis treatments are predominantly bone-resorbing drugs that are associated with several side effects. The use of stem cells for tissue regeneration has raised great hope in various fields of medicine, including musculoskeletal disorders. Stem cell therapy for osteoporosis could potentially reduce the susceptibility of fractures and augment lost mineral density by either increasing the numbers or restoring the function of resident stem cells that can proliferate and differentiate into bone-forming cells. Such osteoporosis therapies can be carried out by exogenous introduction of mesenchymal stem cells (MSCs), typically procured from bone marrow, adipose, and umbilical cord blood tissues or through treatments with drugs or small molecules that recruit endogenous stem cells to osteoporotic sites. The main hurdle with cell-based osteoporosis therapy is the uncertainty of stem cell fate and biodistribution following cell transplantation. Therefore, future advancements will focus on long-term engraftment and differentiation of stem cells at desired bone sites for tangible clinical outcome. PMID:24407712
Antebi, Ben; Pelled, Gadi; Gazit, Dan
Mesenchymal stem cells (MSCs) have drawn great interest in the field of regenerative medicine, for cell replacement, immunomodulatory, and gene therapies. It has been shown that these multipotent stromal cells can be isolated from tissues such as bone marrow, adipose tissue, trimester amniotic tissue, umbilical cord blood, and deciduous teeth and can be expanded in adherent culture. They have the capacity to differentiate into cells of the connective tissue lineages in vitro and contribute to tissue parenchyma in vivo. However, proper in vitro manipulation of MSCs is a key issue to reveal a potential therapeutic benefit following transplantation into the patients. This chapter summarizes some of the essential protocols and assays used at our laboratory for the isolation, culture, differentiation, and characterization of mesenchymal stem cells from the bone marrow and adipose tissue. PMID:24473777
Odabas, Sedat; Elçin, A Eser; Elçin, Y Murat
The nuclei of naive mouse embryonic stem cells that are transitioning towards differentiation expand when the cells are stretched and contract when they are compressed. What drives this auxetic phenotype is, however, unclear.
Extended Abstract?-Cell replacement therapy via islet transplantation has received renewed interest due to the recent improved success. In order to make such a therapy available to more than a few of the thousands of patients with diabetes, new sources of insulin-producing cells must be readily available. The most promising sources are stem cells, with efforts of deriving new ?-cells from
Embryonic stem (ES) cells secrete some soluble factors which may affect the differentiation potential of adult stem cells toward different lineages. In the present study, we evaluated neural differentiation of mouse adipose tissue-derived stem cells (ADSCs) following coculture with ES cells. For this purpose, ADSCs were induced in a medium supplemented with a synthetic serum replacement and various concentrations of retinoic acid (RA). Then, third-passaged ADSCs were indirectly cocultured with ES cells, and the expression levels of pluripotency markers, OCT4 and Sox2, mesenchymal stem cell markers, CD73 and CD105, and proliferating cell nuclear antigen (PCNA), were assessed in the cocultured ADSCs. Moreover, the control and cocultured ADSCs were differentiated with or without RA treatment. We showed here that 2-week differentiated ADSCs expressed several neuron-specific genes, and RA treatment improved neural differentiation of the ADSCs. The expression levels of OCT4, Sox2 and PCNA were upregulated in the cocultured ADSCs. Moreover, coculture with the ES cells significantly improved neural differentiation of the ADSCs. Treatment of the cocultured ADSCs with RA diminished the expression of neural maturation markers. Coculture with the ES cells efficiently improves neural differentiation of the ADSCs. Non-contact coculture with the ES cells may be used as an efficient strategy to improve differentiation potential of adult stem cells for developmental studies and regenerative medicine. PMID:24814017
Bahmani, L; Taha, M F; Javeri, A
Abstract—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
Toren Finkel; Roberto Bolli; Donald Orlic; Jonathan M. Hill; Andrew E. Arai
The keratinocyte cell compartment in the continuously renewing epidermis of the skin is maintained by undifferentiated, self-renewing\\u000a stem cells. We show that a small subpopulation of epidermal stem cells (EpiSCs) have the capacity to integrate into multiple\\u000a tissues. These EpiSCs can change their phenotype in direct response of changes in cytokines in vitro, changes in cocultured\\u000a cells, after injection into
Jackie R. Bickenbach; Matthew M. Stern
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
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
Despite advancements made in our understanding of ocular biology, therapeutic options for many debilitating retinal diseases remain limited. Stem cell-based therapies are a potential avenue for treatment of retinal disease, and this mini-review will focus on current research in this area. Cellular therapies to replace retinal pigmented epithelium (RPE) and/or photoreceptors to treat age-related macular degeneration (AMD), Stargardt's macular dystrophy, and retinitis pigmentosa are currently being developed. Over the past decade, significant advancements have been made using different types of human stem cells with varying capacities to differentiate into these target retinal cell types. We review and evaluate pluripotent stem cells, both human embryonic stem cells and human induced pluripotent stem cells, as well as protocols for differentiation of ocular cells, and culture and transplant techniques that might be used to deliver cells to patients. PMID:21520078
Rowland, Teisha J; Buchholz, David E; Clegg, Dennis O
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.
Many tissues of the body cannot only repair themselves, but also self-renew, a property mainly due to stem cells and the various mechanisms that regulate their behavior. Stem cell biology is a relatively new field. While advances are slowly being realized, stem cells possess huge potential to ameliorate disease and counteract the aging process, causing its speculation as the next panacea. Amidst public pressure to advance rapidly to clinical trials, there is a need to understand the biology of stem cells and to support basic research programs. Without a proper comprehension of how cells and tissues are maintained during the adult life span, clinical trials are bound to fail. This review will cover the basic biology of stem cells, the various types of stem cells, their potential function, and the advantages and disadvantages to their use in medicine. We will next cover the role of G-protein coupled receptors in the regulation of stem cells and their potential in future clinical applications.
DOZE, VAN A.; PEREZ, DIANNE M.
The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic cells in several ways. These cells aggregated in structures similar, but not identical,
Yuichi Hori; Ingrid C. Rulifson; Bernette C. Tsai; Jeremy J. Heit; John D. Cahoy; Seung K. Kim
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 therapy seems natural enough and is unlikely to be morally suspect. Nevertheless, we feel morally uncertain when we consider giving this type of therapy to patients who would not naturally receive it. Much has been written about the ethics of stem cell research and therapy; this paper will focus on how recent advances in biotechnology and biological understandings of development narrow the debate. Here, the author briefly reviews current stem cell research practices, revisits the natural stem cell therapy case for moral evaluation, and ultimately demonstrates the importance of permissible stem cell research and therapy, even absent an agreement about the definition of when embryonic life begins. Although one promising technology, blighted ovum utilisation, uses fertilised but developmentally bankrupt eggs, it is argued that utilisation of unfertilised eggs to derive totipotent stem cells obviates the moral debate over when life begins. There are two existing technologies that fulfil this criterion: somatic cell nuclear transfer and parthenogenic stem cell derivation. Although these technologies are far from therapeutic, concerns over the morality of embryonic stem cell derivation should not hinder their advancement. PMID:16574879
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 therapy seems natural enough and is unlikely to be morally suspect. Nevertheless, we feel morally uncertain when we consider giving this type of therapy to patients who would not naturally receive it. Much has been written about the ethics of stem cell research and therapy; this paper will focus on how recent advances in biotechnology and biological understandings of development narrow the debate. Here, the author briefly reviews current stem cell research practices, revisits the natural stem cell therapy case for moral evaluation, and ultimately demonstrates the importance of permissible stem cell research and therapy, even absent an agreement about the definition of when embryonic life begins. Although one promising technology, blighted ovum utilisation, uses fertilised but developmentally bankrupt eggs, it is argued that utilisation of unfertilised eggs to derive totipotent stem cells obviates the moral debate over when life begins. There are two existing technologies that fulfil this criterion: somatic cell nuclear transfer and parthenogenic stem cell derivation. Although these technologies are far from therapeutic, concerns over the morality of embryonic stem cell derivation should not hinder their advancement.
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
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.
Experiments have shown that the physical characteristics of the matrix surrounding a stem cell can affect its behaviour. This picture gets further complicated by studies of stem cells and their differentiated counterparts that show that the cells' own softness also has a clear role in how they respond to stress.
Holle, Andrew W.; Engler, Adam J.
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 cells from human skeletal muscle that is able to proliferate for extended periods of time as floating clusters of rounded cells, termed 'myospheres' or myosphere-derived progenitor cells (MDPCs). The phenotypic characteristics and functional properties of these cells were determined using reverse transcription-polymerase chain reaction (RT-PCR), flow cytometry and immunocytochemistry. Our results showed that these cells are clonogenic, express skeletal progenitor cell markers Pax7, ALDH1, Myod, and Desmin and the stem cell markers Nanog, Sox2, and Oct3/4 significantly elevated over controls. They could be maintained proliferatively active in vitro for more than 20 weeks and passaged at least 18 times, despite an average donor-age of 63 years. Individual clones (4.2%) derived from single cells were successfully expanded showing clonogenic potential and sustained proliferation of a subpopulation in the myospheres. Myosphere-derived cells were capable of spontaneous differentiation into myotubes in differentiation media and into other mesodermal cell lineages in induction media. We demonstrate here that direct culture and expansion of stem cells from human skeletal muscle is straightforward and reproducible with the appropriate technique. These cells may provide a viable resource of adult stem cells for future therapies of disease affecting skeletal muscle or mesenchymal lineage derived cell types.
Wei, Yan [Department of Otolaryngology, Head and Neck Surgery Charite-Universitaetsmedizin Berlin, Berlin (Germany) [Department of Otolaryngology, Head and Neck Surgery Charite-Universitaetsmedizin Berlin, Berlin (Germany); Department of Otolaryngology, Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou (China); Li, Yuan [Department of Otolaryngology, Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou (China)] [Department of Otolaryngology, Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guang Zhou (China); Chen, Chao; Stoelzel, Katharina [Department of Otolaryngology, Head and Neck Surgery Charite-Universitaetsmedizin Berlin, Berlin (Germany)] [Department of Otolaryngology, Head and Neck Surgery Charite-Universitaetsmedizin Berlin, Berlin (Germany); Kaufmann, Andreas M. [Clinic for Gynecology CCM/CBF, Charite-Universitaetsmedizin Berlin, Berlin (Germany)] [Clinic for Gynecology CCM/CBF, Charite-Universitaetsmedizin Berlin, Berlin (Germany); Albers, Andreas E., E-mail: email@example.com [Department of Otolaryngology, Head and Neck Surgery Charite-Universitaetsmedizin Berlin, Berlin (Germany)
Significance In this review, we summarize the current literature regarding the isolation and characterization of dental tissue-derived stem cells and address the potential of these cell types for use in regenerative cell transplantation therapy. Recent Advances Looking forward, platforms for the delivery of stem cells via scaffolds and the use of growth factors and cytokines for enhancing dental stem cell self-renewal and differentiation are discussed. Critical Issues We aim to understand the developmental origins of dental tissues in an effort to elucidate the molecular pathways governing the genesis of somatic dental stem cells. The advantages and disadvantages of several dental stem cells are discussed, including the developmental stage and specific locations from which these cells can be purified. In particular, stem cells from human exfoliated deciduous teeth may act as a very practical and easily accessibly reservoir for autologous stem cells and hold the most value in stem cell therapy. Dental pulp stem cells and periodontal ligament stem cells should also be considered for their triple lineage differentiation ability and relative ease of isolation. Further, we address the potentials and limitations of induced pluripotent stem cells as a cell source in dental regenerative. Future Directions From an economical and a practical standpoint, dental stem cell therapy would be most easily applied in the prevention of periodontal ligament detachment and bone atrophy, as well as in the regeneration of dentin-pulp complex. In contrast, cell-based tooth replacement due to decay or other oral pathology seems, at the current time, an untenable approach.
Feng, Ruoxue; Lengner, Chistopher
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
Cancer stem cells have recently been proposed to play a significant role in the initiation and propagation of tumor cells.\\u000a They display indefinite self-renewal capacity and multilineage potential as well as an excessive proliferation capacity. Cancer\\u000a stem cells are quiescent with low mitotic frequencies. They seem to be relatively radioresistant and have been demonstrated\\u000a to increase in relative amount following
David Eriksson; Katrine Riklund; Lennart Johansson; Torgny Stigbrand
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.
As an example of the burgeoning importance of stem cell therapy, this past month the California Institute for Regenerative Medicine (CIRM) has approved $70 million to create a new network of stem cell clinical trial centers. Much work in the last decade has been devoted to developing the use of autologous and allogeneic adult stem cell transplants to treat a number of conditions, including heart attack, dementia, wounds, and immune system-related diseases. The standard model teaches us that adult stem cells exists throughout most of the body and provide a means to regenerate and repair most tissues through replication and differentiation. Although we have often witnessed the medical cart placed in front of the scientific horse in the development of stem cell therapies outside of academic circles, great strides have been made, such as the use of purified stem cells1 instead of whole bone marrow transplants in cancer patients, where physicians avoid re-injecting the patients with their own cancer cells.2 We most often think of stem cell therapy acting to regenerate tissue through replication and then differentiation, but recent studies point to the dramatic effects adult stem cells exert in the repair of various tissues through the release of paracrine and autocrine substances, and not simply through differentiation. Indeed, up to 80% of the therapeutic effect of adult stem cells has been shown to be through paracrine mediated actions.3 That is, the collected types of molecules released by the stem cells, called the secretome, or stem cell released molecules (SRM), number in the 100s, including proteins, microRNA, growth factors, antioxidants, proteasomes, and exosomes, and target a multitude of biological pathways through paracrine actions. The composition of the different molecule types in SRM is state dependent, and varies with cell type and conditions such as age and environment.
As an example of the burgeoning importance of stem cell therapy, this past month the California Institute for Regenerative Medicine (CIRM) has approved $70 million to create a new network of stem cell clinical trial centers. Much work in the last decade has been devoted to developing the use of autologous and allogeneic adult stem cell transplants to treat a number of conditions, including heart attack, dementia, wounds, and immune system-related diseases. The standard model teaches us that adult stem cells exists throughout most of the body and provide a means to regenerate and repair most tissues through replication and differentiation. Although we have often witnessed the medical cart placed in front of the scientific horse in the development of stem cell therapies outside of academic circles, great strides have been made, such as the use of purified stem cells(1) instead of whole bone marrow transplants in cancer patients, where physicians avoid re-injecting the patients with their own cancer cells.(2) We most often think of stem cell therapy acting to regenerate tissue through replication and then differentiation, but recent studies point to the dramatic effects adult stem cells exert in the repair of various tissues through the release of paracrine and autocrine substances, and not simply through differentiation. Indeed, up to 80% of the therapeutic effect of adult stem cells has been shown to be through paracrine mediated actions.(3) That is, the collected types of molecules released by the stem cells, called the secretome, or stem cell released molecules (SRM), number in the 100s, including proteins, microRNA, growth factors, antioxidants, proteasomes, and exosomes, and target a multitude of biological pathways through paracrine actions. The composition of the different molecule types in SRM is state dependent, and varies with cell type and conditions such as age and environment. PMID:24567776
New technologies that facilitate solid alveolar ridge augmentation are receiving considerable attention in the field of prosthodontics because of the growing requirement for esthetic and functional reconstruction by dental implant treatments. Recently, several studies have demonstrated potential advantages for stem-cell-based therapies in regenerative treatments. Mesenchymal stem/stromal cells (MSCs) are now an excellent candidate for tissue replacement therapies, and tissue engineering approaches and chair-side cellular grafting approaches using autologous MSCs represent the clinical state of the art for stem-cell-based alveolar bone regeneration. Basic studies have revealed that crosstalk between implanted donor cells and recipient immune cells plays a key role in determining clinical success that may involve the recently observed immunomodulatory properties of MSCs. Part II of this review first overviews progress in regenerative dentistry to consider the implications of the stem cell technology in dentistry and then highlights cutting-edge stem-cell-based alveolar bone regenerative therapies. Factors that affect stem-cell-based bone regeneration as related to the local immune response are then discussed. Additionally, pre-clinical stem cell studies for the regeneration of teeth and other oral organs as well as possible applications of MSC-based immunotherapy in dentistry are outlined. Finally, the marketing of stem cell technology in dental stem cell banks with a view toward future regenerative therapies is introduced. PMID:23137671
Egusa, Hiroshi; Sonoyama, Wataru; Nishimura, Masahiro; Atsuta, Ikiru; Akiyama, Kentaro
Researchers at UCLA have identified a new stem cell that participates in the repair of the large airways of the lungs, which play a vital role in protecting the body from infectious agents and toxins in the environment.
Soft dental tissues have been identified as easily accessible sources of multipotent postnatal stem cells. Dental stem cells are mesenchymal stem cells (MSC) capable of differentiating into at least three distinct cell lineages: osteo/odontogenic, adipogenic and neurogenic. They express various markers including those specific for MSC, embryonic stem cells and neural cells. Five different types of dental stem cells have been isolated from mature and immature teeth: dental pulp stem cells, stem cells from exfoliated deciduous teeth, periodontal ligament stem cells, stem cells from apical papilla and dental follicle progenitor cells. Dental stem cells may be used in dental tissue engineering including dental, enamel and periodontal tissue regeneration. They could also be used as a promising tool in potential treatment of neurodegenerative, ischemic and immune diseases. PMID:24446280
Bojic, Sanja; Volarevic, Vladislav; Ljujic, Biljana; Stojkovic, Miodrag
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;)
While human pluripotent stem cells are attractive sources for cell-replacement therapies, a major concern remains regarding their tumorigenic potential. Thus, safety assessment of human pluripotent stem cell-based products in terms of tumorigenicity is critical. Previously we have identified a pluripotent stem cell-specific lectin probe rBC2LCN recognizing hyperglycosylated podocalyxin as a cell surface ligand. Here we demonstrate that hyperglycosylated podocalyxin is secreted from human pluripotent stem cells into cell culture supernatants. We establish a sandwich assay system, named the GlycoStem test, targeting the soluble hyperglycosylated podocalyxin using rBC2LCN. The GlycoStem test is sufficiently sensitive and quantitative to detect residual human pluripotent stem cells. This work provides a proof of concept for the noninvasive and quantitative detection of tumorigenic human pluripotent stem cells using cell culture supernatants. The developed method should increase the safety of human pluripotent stem cell-based cell therapies.
Tateno, Hiroaki; Onuma, Yasuko; Ito, Yuzuru; Hiemori, Keiko; Aiki, Yasuhiko; Shimizu, Madoka; Higuchi, Kumiko; Fukuda, Masakazu; Warashina, Masaki; Honda, Susumu; Asashima, Makoto; Hirabayashi, Jun
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
Pancreatic ?-cell failure underlies type 1 diabetes; it also contributes in an essential way to type 2 diabetes. ?-Cell replacement is an important component of any cure for diabetes. The current options of islet and pancreas transplantation are not satisfactory as definitive forms of therapy. Here, we review strategies for induced de novo pancreatic ?-cell formation, which depend on the targeted differentiation of cells into pancreatic ?-cells. With this objective in mind, one can manipulate the fate of three different types of cells: 1) from terminally differentiated cells, e.g. exocrine pancreatic cells, into ?-cells; 2) from multipotent adult stem cells, e.g. hepatic oval cells, into pancreatic islets; and 3) from pluripotent stem cells, e.g. embryonic stem cells and induced pluripotent stem cells, into ?-cells. We will examine the pros and cons of each strategy as well as the hurdles that must be overcome before these approaches to generate new ?-cells will be ready for clinical application.
Yechoor, Vijay; Chan, Lawrence
The aim of stem cell therapy for Parkinson's disease is to reconstruct nigro-striatal neuronal pathways using endogenous neural stem/precursor cells or grafted dopaminergic neurons. As an alternative, transplantation of stem cell-derived dopaminergic neurons into the striatum has been attempted, with the aim of stimulating local synapse formation and/or release of dopamine and cytokines from grafted cells. Candidate stem cells include neural stem/precursor cells, embryonic stem cells and other stem/precursor cells. Among these, embryonic stem cells are pluripotent cells that proliferate extensively, making them a good potential donor source for transplantation. However, tumor formation and ethical issues present major problems for embryonic stem cell therapy. This review describes the current status of stem cell therapy for Parkinson's disease, as well as future research approaches from a clinical perspective. PMID:17563250
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
The hypothesis in this study is that the stem stiffness-to-bone stiffness ratio influences the incidence and type of bone remodeling and fixation with cemented total hip arthroplasty. Ninety-one patients with 99 hips had cemented stems using 3 different anatomic porous replacement designs. The APR I and APR II titanium stems with proximal porous coating on the proximal one fourth of
Zhinian Wan; Lawrence D. Dorr; Terry Woodsome; Anil Ranawat; Michael Song
The field of stem cell biology continues to evolve with the ongoing characterization of multiple types of stem cells with their inherent potential for experimental and clinical application. Mesenchymal stem cells (MSC) are one of the most promising stem cell types due to their availability and the relatively simple requirements for in vitro expansion and genetic manipulation. Multiple populations described
Elisabeth H. Javazon; Kirstin J. Beggs; Alan W. Flake
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
versus quiescence? Not surprisingly, resear, 1998 John Wiley & (e) How are different stem cell fates determined? (f ) Sons, Inc. J Neurobiol 36: 111 ? 127, 1998 How ‘‘plastic’’ are different neural stem cell fates? Keywords: neuroblast; asymmetric division; Prospero; (g) How do neural stem cells produce different prog- Miranda; Inscuteable eny? and (h) What regulates stem cell proliferation
Chris Q. Doe; Sal Fuerstenberg
There is worldwide enthusiasm for the prospect of some kind of cellular transplant therapy for repair of failing organs. The olfactory mucosa of a patient's nose is easily biopsied to provide a ready source of multipotent cells. In this article we address practical issues pertinent to using olfactory neural stem cells for tissue repair. These cells are emerging as potentially most significant candidates for human tissue repair strategies. Previously we have shown that stem cells from olfactory mucosa are multipotent. As well, we have recently published three potential clinical applications. Their expression of dopaminergic markers in vitro and in a Parkinson's rat transplant model has been demonstrated. Their conversion to chondrogenic phenotype in vitro and in vivo has also been described, as has their transplant into a rat model of cardiac infarction. Here we examine in detail the biology of the olfactory neural stem cell using the rat as our animal model cell source. We establish its presence by examining self-renewal capacity and for phenotypic acquisition in inductive circumstances. We determine its frequency within the cell population and show that our culture system selects for this putative stem cell. Our studies demonstrate that adult olfactory stem cells, when transplanted into an environmental niche different from that of their origin, are able to demonstrate multipotency by acquiring the phenotype of the resident cells. We investigate how immediate the instruction need be. We test the hypothesis that olfactory neurospheres contain stem cells whose capacity for differentiation is triggered by signals of the immediate environmental niche. Significantly, of importance to any tissue regeneration endeavor, stem cell numbers were shown to be enriched by our culture methods. This was confirmed whether measured by sphere-forming capacity or differentiation response rate. PMID:21535908
Wetzig, Andrew; Mackay-Sim, Alan; Murrell, Wayne
Glioblastoma multiforme represents one of the most common brain cancers with a rather heterogeneous cellular composition, as indicated by the term "multiforme". Recent reports have described the isolation and identification of cancer neural stem cells from human adult glioblastoma multiforme, which possess the capacity to establish, sustain, and expand these tumours, even under the challenging settings posed by serial transplantation experiments. Our study focused on the distribution of neural cancer stem cells inside the tumour. The study is divided into three phases: removal of tumoral specimens in different areas of the tumour (centre, periphery, marginal zone) in an operative room equipped with a 1.5 T scanner; isolation and characterization of neural cancer stem cells from human adult glioblastoma multiforme; identification of neural cancer stem cell distribution inside the tumour. PMID:24750704
Rispoli, Rossella; Conti, Carlo; Celli, Paolo; Caroli, Emanuela; Carletti, Sandro
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...
Samantha and her husband Brad have two children, conceived with the help of in vitro fertilization treatments. After viewing a TV program on stem cells and their potential medical uses, Samantha is convinced that they should donate the remaining frozen embryos they have to medical research, an idea Brad strongly objects to. The case teaches about stem cells and their medical applications as well as the ethical dilemmas posed by their use.
Yaich, Lauren E.
As most of our readers no doubt know, President Bush made a determination on federal funding for embryonic stem cell research in August 2001, agreeing to release federal funds for research involving already existing stem cell lines. Information on this contentious topic is available at CNN's in-depth special, which features articles, analysis, video clips, and message boards devoted to the many aspects of the debate.
The immobilization of cells into polymeric scaffolds releasing therapeutic factors, such as alginate microcapsules, has been widely employed as a drug-delivery system for numerous diseases for many years. As a result of the potential benefits stem cells offer, during recent decades, this type of cell has gained the attention of the scientific community in the field of cell microencapsulation technology and has opened many perspectives. Stem cells represent an ideal tool for cell immobilization and so does alginate as a biomaterial of choice in the elaboration of these biomimetic scaffolds, offering us the possibility of benefiting from both disciplines in a synergistic way. This review intends to give an overview of the many possibilities and the current situation of immobilized stem cells in alginate bioscaffolds, showing the diverse therapeutic applications they can already be employed in; not only drug-delivery systems, but also tissue engineering platforms. PMID:22838071
Garate, Ane; Murua, Ainhoa; Orive, Gorka; Hernández, Rosa M; Pedraz, Jose Luis
Stem cells have enormous potential for therapeutic application because of their ability to self-renew and differentiate into different cell types. Gonads, which consist of somatic cells and germ cells, are the only organs capable of transmitting genetic materials to the offspring. Germ-line stem cells and somatic stem cells have been found in the testis; however, the presence of stem cells in the ovary remains controversial. In this review, we discuss studies focusing on whether stem cell properties are present in the different cell types of male and female gonads and their implications on stem cell research.
Liu, Chia-Feng; Barsoum, Ivraym; Gupta, Rupesh; Hofmann, Marie-Claude; Yao, Humphrey Hung-Chang
... of stem cells for transplant Types of stem cell transplants for treating cancer In a typical stem ... from your identical twin or triplet Autologous stem cell transplants These stem cells come from you alone. ...
The cornea consists of three main layers: an outer surface epithelium, the stroma, and the endothelium. A clear cornea is necessary for optimal vision and is maintained and repaired from limbal epithelial stem cells located in the limbus between the cornea and the sclera. Diseases and injury may result in deficiency of the stem cells impairing their ability to renew the corneal epithelium. Patients with limbal stem cell deficiency experience chronic pain and ultimately blindness. Attempts to treat the disease are based on replacement of the stem cells by transplantation or by culturing the stem cells. We here review the proteomic techniques that so far have been used to approach characterization of limbal stem cells and markers to identify them. It is apparent that the field is in a rather inchoate state due to the scarcity and relative inaccessibility of the stem cells. However, the importance of revealing limbal stem cell biology and identifying stem cell biomarkers calls for greater use of emerging methodology. Strategies for future studies are discussed. PMID:24497450
Honoré, Bent; Vorum, Henrik
Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells,
Mikhail Spivakov; Amanda G. Fisher
Radiation injury to skin results in a variety of deterministic effects including inflammatory reactions and cell depletion leading to distinct clinical symptoms following a defined time pattern. Therapeutic approaches are still limited, a complete restitution of affected areas is so far impossible. In the last few years increasing experimental knowledge about acquisition and administration of autologous stem cells also in the field of radiation injuries has been obtained. Evidence reviewed in this article shows that the beneficial effects of stem cell transplantation are not necessarily due to the replacement of damaged cells by transplanted cells but most probably due in the most part to a paracrine effect. Transplanted cells secrete bioactive factors that initiate the stimulation of the host stem cells to regenerate the damaged tissues. Transplanted stem cells produce trophic factors which aid the systemic healing of the victims. Furthermore, administration of stem cell secretomes in the form of conditioned media containing microvesicles or exosomes can be as effective as administering the stem cells. This hypothesis is supported by findings that cell-free derivatives from hMSCs were useful for wound healing purposes and could circumvent the need for intact cells. Furthermore, the beneficial effect of MSC injection on reperfusion and tissue damage in a mouse model of hind limb ischemia could be attributed to paracrine mechanisms with local release of arteriogenic cytokines. Further evaluation of the paracrine potential of autologous stem cells may open new means for treatment of acute as well as chronic sequelae of cutaneous radiation injuries. PMID:24337306
The Drosophila lymph gland, the source of adult hemocytes, is established by mid-embryogenesis. During larval stages, a pool of pluripotent hemocyte precursors differentiate into hemocytes that are released into circulation upon metamorphosis or in response to immune challenge. This process is controlled by the posterior signaling center (PSC), which is reminiscent of the vertebrate hematopoietic stem cell niche. Using lineage analysis, we identified bona fide hematopoietic stem cells (HSCs) in the lymph glands of embryos and young larvae, which give rise to a hematopoietic lineage. These lymph glands also contain pluripotent precursor cells that undergo a limited number of mitotic divisions and differentiate. We further find that the conserved factor Zfrp8/PDCD2 is essential for the maintenance of the HSCs, but dispensable for their daughter cells, the pluripotent precursors. Zfrp8/PDCD2 is likely to have similar functions in hematopoietic stem cell maintenance in vertebrates. PMID:20023157
Minakhina, Svetlana; Steward, Ruth
A flexible space solar cell coverglass replacement called Pseudomorphic Glass (PMG) has been under investigation in hopes of providing a robust, flexible, high transmissivity replacement for conventional coverglass. PMG is composed of conventional cover glass and/or fused silica in the form of small spheres incorporated in a variety of polymer matrices. The glass spheres provide the primary radiation protection and the polymer matrix provides the mechanical integrity. PMG development has recently focused on technologies for providing the electrical conductivity required to dissipate environmental charging, even in the presence of electric propulsion plumes.
Levin, Zach S.; Wilt, David M.; Hoffman, Ryan; Ferguson, Dale
The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation. PMID:20882052
Gögel, S; Gubernator, M; Minger, S L
Characterization of pluripotent stem cells is required for the registration of stem cell lines and allows for an impartial and objective comparison of the results obtained when generating multiple lines. It is therefore crucial to establish specific, fast and reliable protocols to detect the hallmarks of pluripotency. Such protocols should include immunocytochemistry (takes 2 d), identification of the three germ layers in in vitro-derived embryoid bodies by immunocytochemistry (immunodetection takes 3 d) and detection of differentiation markers in in vivo-generated teratomas by immunohistochemistry (differentiation marker detection takes 4 d). Standardization of the immunodetection protocols used ensures minimum variations owing to the source, the animal species, the endogenous fluorescence or the inability to collect large amounts of cells, thereby yielding results as fast as possible without loss of quality. This protocol provides a description of all the immunodetection procedures necessary to characterize mouse and human stem cell lines in different circumstances. PMID:23306458
Martí, Mercč; Mulero, Lola; Pardo, Cristina; Morera, Cristina; Carrió, Meritxell; Laricchia-Robbio, Leopoldo; Esteban, Concepcion Rodriguez; Izpisua Belmonte, Juan Carlos
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
Physical cues from the extracellular environment influence the lineage commitment of stem cells. Now, experiments on human mesenchymal stem cells cultured on photodegradable hydrogels show that the cells' fate can also be determined by past physical environments.
Eyckmans, Jeroen; Chen, Christopher S.
Hematopoietic stem cells (HSCs) possess the ability to self-renew and to differentiate to mature progeny along multiple different hematopoietic lineages. The function of HSCs depends upon the signals from surrounding cells found within the highly specialized microenvironment termed the hematopoietic stem cell niche. Understanding and exploiting the HSC niche is a goal of basic scientists and clinicians alike. Recent studies have focused on defining the cellular components and molecular factors critical to this microenvironment. Here we review recent findings, discuss unresolved questions, and examine the clinical implications of our current knowledge of the HSC niche.
Park, Dongsu; Sykes, David B.; Scadden, David T.
Human embryonic stem cells have been a major topic in science, medicine, and religion since their discovery in 1998. However, due to the complex discourse and rhetoric of scientific language, debate has remained within the professional realm via "expert bioethics." Using the tenets of pragmatism, the author examines the need to move the debate to society as a whole and disentangle the stem cell debate from the ideologies of the human cloning and abortion debates. Opening this issue to a societal debate will advance societal growth, resulting in informed decisions on moral issues, funding, or regulation associated with hES cell research. PMID:12755109
Sitko, Bradley J
Background: Autologous, and in some cases allogeneic, hemopoietic stem cells (HSC) are stored for varying periods of time prior to infusion. For periods of greater than 48 h, storage requires cryopreservation. It is essential to optimize cell storage and ensure the quality of the product for subsequent reinfusion. Methods: A number of important variables may affect the subsequent quality of infused HSC and therapeutic cells (TC). This review discusses these and also reviews the regulatory framework that now aims to ensure the quality of stem cells and TC for transplantation. Results: Important variables included cell concentration, temperature, interval from collection to cryopreservation, manipulations performed. They also included rate of freezing and whether controlled-rate freezing was employed. Parameters studied were type of cryoprotectant utilized [dimethyl sulphoxide (DMSO) is most commonly used, sometimes in combination with hydroxyethyl starch (HES)]; and storage conditions. It is also important to assess the quality of stored stem cells. Measurements employed included the total cell count (TNC), mononuclear cell count (MNC), CD34+ cells and colony-forming units - granulocyte macrophage (CFU-GM). Of these, TNC and CD34+ are the most useful. However, the best measure of the quality of stored stem cells is their subsequent engraftment. The quality systems used in stem cell laboratories are described in the guidance of the Joint Accreditation Committee of ISCT (Europe) and the EBMT (JACIE) and the EU Directive on Tissues and Cells plus its supporting commission directives. Inspections of facilities are carried out by the appropriate national agencies and JACIE. Conclusion: For high-quality storage of HSC and TC, processing facilities should use validated procedures that take into account critical variables. The quality of all products must be assessed before and after storage.
Pamphilon, Derwood; Mijovic, Aleksandar
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.
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-embryonic 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. PMID:22907257
Beane, Olivia S; Darling, Eric M
Murine embryonic stem (ES) cells have become an indispensable tool for investigating genetic function both in vitro and, importantly, in vivo. Recent advances, including tetraploid aggregation, new site-specific recombinases and RNAi, have enabled more sophisticated manipulation of the ES cell genome. For instance, it is now possible to control gene expression in both a temporally and spatially restricted manner. Such
J. S. Draper; A. Nagy
Retinal degenerative diseases constitute a major cause of irreversible blindness in the world. Stem cell-based therapies offer hope for these patients at risk of or suffering from blindness due to the deterioration of the neural retina. Various sources of stem cells are currently being investigated, ranging from human embryonic stem cells to adult-derived induced pluripotent stem cells as well as human Müller stem cells, with the first clinical trials to investigate the safety and tolerability of human embryonic stem cell-derived retinal pigment epithelium cells having recently commenced. This review aims to summarize the latest advances in the development of stem cell strategies for the replacement of retinal neurons and their supportive cells, the retinal pigment epithelium (RPE) affected by retinal degenerative conditions. Particular emphasis will be given to the advances in stem cell transplantation and the challenges associated with their translation into clinical practice.
Becker, Silke; Jayaram, Hari; Limb, G. Astrid
Retinal degenerative diseases constitute a major cause of irreversible blindness in the world. Stem cell-based therapies offer hope for these patients at risk of or suffering from blindness due to the deterioration of the neural retina. Various sources of stem cells are currently being investigated, ranging from human embryonic stem cells to adult-derived induced pluripotent stem cells as well as human Müller stem cells, with the first clinical trials to investigate the safety and tolerability of human embryonic stem cell-derived retinal pigment epithelium cells having recently commenced. This review aims to summarize the latest advances in the development of stem cell strategies for the replacement of retinal neurons and their supportive cells, the retinal pigment epithelium (RPE) affected by retinal degenerative conditions. Particular emphasis will be given to the advances in stem cell transplantation and the challenges associated with their translation into clinical practice. PMID:24710533
Becker, Silke; Jayaram, Hari; Limb, G Astrid
Mesenchymal stem cells (MSCs) have multi-differentiation potency, and enhance wound healing in various kinds of disease. Recently MSC not only differentiate into tissue-forming cells, but also secrete various kinds of cytokines and chemokines that are anti-apoptotic, immunomodulatory, angiogenic, and the cell-mobilizing to influence extracellular environment. In addition, we show that MSC has a novel intercellular communication mechanism. It hopes to suggest ways to make safer and reliable usage of MSC in bone regeneration. PMID:24681503
Komaki, Motohiro; Iwasaki, Kengo; Morita, Ikuo
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.
\\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
Stem cells, including both pluripotent stem cells and multipotent somatic stem cells, hold great potential for interrogating the mechanisms of tissue development, homeostasis and pathology, and for treating numerous devastating diseases. Establishment of in vitro platforms to faithfully maintain and precisely manipulate stem cell fates is essential to understand the basic mechanisms of stem cell biology, and to translate stem cells into regenerative medicine. Chemical approaches have recently provided a number of small molecules that can be used to control cell self-renewal, lineage differentiation, reprogramming and regeneration. These chemical modulators have been proven to be versatile tools for probing stem cell biology and manipulating cell fates toward desired outcomes. Ultimately, this strategy is promising to be a new frontier for drug development aimed at endogenous stem cell modulation.
Li, Wenlin; Jiang, Kai; Wei, Wanguo; Shi, Yan; Ding, Sheng
The adult vertebrate central nervous system (CNS) consists of four major differentiated cell types: neurons, astrocytes, oligodendrocytes and ependymal cells. Historically, there has been a disagreement on how these differentiated cell types are generated in the CNS. Progress remains hindered by the complexity of cell structure in this system, the lack of specific cell surface markers to identify distinct cell
D L Clarke
The relationship between cell growth (cell mass increase over time) and cell division is poorly understood in animal stem cells. Recent studies in several Drosophila stem cell types have provided the tools to interrogate this relationship. In several cases (brat, mei-P26, pros, bam, lethal giant larvae, polo), mutations have been defined that trigger tumorous overproliferation of progenitor cells and reveal how unrestricted self-renewing capacity is controlled. Moreover, microRNAs have been discovered as essential regulators of stem cell division rate and identity, suggesting that stem cell self-renewal depends on protein translational control. Biosynthetic capacity has also been found to be limiting for stem cell division rates. Finally, asymmetric cell division can impose dominant differentiation signals in a stem cell's daughter, and this can inhibit the stem cell-specific proliferation signature and lock in cell cycle exit. PMID:18996190
Kohlmaier, Alexander; Edgar, Bruce A
The isolation and culture of both embryonic and extraembryonic stem cells provide an enormous opportunity to study the molecular processes that establish and maintain lineage-specific, monoallelic patterns of gene expression. This chapter describes the isolation an culture of trophectoderm stem cells from mouse blastocyst stage embryos. Using this powerful in vitro system, scientists can now begin to tease apart the epigenetic processes that result in placental patterns of imprinted gene expression and begin to better understand the role these genes play in development and disease.
Golding, Michael C.
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
The ability to identify the donor stem cells following transplantation into injured hearts is critical. This is particularly important in evaluating stem cell survival and lineage differentiation into mature cardiovascular cells. Several approaches have been employed for tracking the donor stem cells, including fluorescent dyes and fluorescent protein gene transfer. Here, we will induce a protocol using lentivirus-mediated green fluorescent protein (GFP) to monitor the fate of donor stem cells following transplantation.
Wang, Yingjie; Zhang, Lan; Pan, Yaohua; Chen, Lijuan; Weintraub, Neal; Tang, Yaoliang
Both hereditary and sporadic breast cancers may develop through dysregulation of self-renewal pathways of normal mammary stem\\u000a cells. Networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewal\\u000a and possibly stem cell aging. Breast cancer susceptibility gene (BRCA1) is a nuclear phosphoprotein expressed in many nuclear\\u000a processes, including stem cell regulator, DNA damage repair,
We studied umbilical cord blood mesenchymal stem cells and compared mesenchymal stem cells derived from umbilical cord blood,\\u000a adipose tissue, and skin. Umbilical cord blood mesenchymal stem cells were characterized morphologically, cytofluorometrically,\\u000a and by their differentiation potential. Umbilical cord blood mesenchymal stem cells did not differ from cells isolated from\\u000a adipose tissue and skin by the main parameters (by morphology,
R. A. Musina; E. S. Bekchanova; A. V. Belyavskii; T. S. Grinenko; G. T. Sukhikh
In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration. Key words:Dental stem cells, regenerative dentistry, mesenchymal stem cells, tissue engineering, stem cells.
Insausti, Carmen-Luisa; Iniesta, Francisca; Blanquer, Miguel; Ramirez, Maria-del-Carmen; Meseguer, Luis; Meseguer-Henarejos, Ana-Belen; Marin, Noemi; Martinez, Salvador; Moraleda, Jose-Maria
Pluripotent stem cells (PSCs), characterized by being able to differentiate into various types of cells, are generally regarded\\u000a as the most promising sources for cell replacement therapies. However, as typical PSCs, embryonic stem cells (ESCs) are still\\u000a far away from human clinics so far due to ethical issues and immune rejection response. One way to avoid such problems is\\u000a to
Huiqun Yin; Heng Wang; Hongguo Cao; Yunhai Zhang; Yong Tao; Xiaorong Zhang
Stem cell therapy has emerged as a promising new approach in almost every medicine specialty. This vast, heterogeneous family of cells are now both naturally (embryonic and adult stem cells) or artificially obtained (induced pluripotent stem cells or iPSCs) and their fates have become increasingly controllable, thanks to ongoing research in this passionate new field. We are at the beginning of a new era in medicine, with multiple applications for stem cell therapy, not only as a monotherapy, but also as an adjunct to other strategies, such as organ transplantation or standard drug treatment. Regrettably, serious preclinical concerns remain and differentiation, cell fusion, senescence and signalling crosstalk with growth factors and biomaterials are still challenges for this promising multidisciplinary therapeutic modality. Severe burns have several indications for stem cell therapy, including enhancement of wound healing, replacement of damaged skin and perfect skin regeneration – incorporating skin appendages and reduced fibrosis –, as well as systemic effects, such as inflammation, hypermetabolism and immunosuppression. The aim of this review is to describe well established characteristics of stem cells and to delineate new advances in the stem cell field, in the context of burn injury and wound healing.
Arno, Anna; Smith, Alexandra H.; Blit, Patrick H.; Shehab, Mohammed Al; Gauglitz, Gerd G.; Jeschke, Marc G.
Loss of vision in severe retinal degenerations often is a result of photoreceptor cell or retinal pigment epithelial cell death or dysfunction. Cell replacement therapy has the potential to restore useful vision for these individuals especially after they have lost most or all of their light-sensing cells in the eye. A reliable, well-characterized source of retinal cells will be needed for replacement purposes. Human embryonic stem cells (ES cells) can provide an unlimited source of replacement retinal cells to take over the function of lost cells in the eye. The author's intent for this review is to provide an historical overview of the field of embryonic stem cells with relation to the retina. The review will provide a quick primer on key pathways involved in the development of the neural retina and RPE followed by a discussion of the various protocols out in the literature for generating these cells from non-human and human embryonic stem cells and end with in vivo application of ES cell-derived photoreceptors and RPE cells. PMID:23880530
Reynolds, Joseph; Lamba, Deepak A
Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.
Vrana, Kent E.; Hipp, Jason D.; Goss, Ashley M.; McCool, Brian A.; Riddle, David R.; Walker, Stephen J.; Wettstein, Peter J.; Studer, Lorenz P.; Tabar, Viviane; Cunniff, Kerrianne; Chapman, Karen; Vilner, Lucy; West, Michael D.; Grant, Kathleen A.; Cibelli, Jose B.
Parkinson's disease (PD) involves the loss of dopamine (DA) neurons, making it the most expected neurodegenerative disease to be treated by cell replacement therapy. Stem cells are a promising source for cell replacement therapy due to their ability to self-renew and their pluripotency\\/multipotency that allows them to generate various types of cells. However, it is challenging to derive midbrain DA
Stem cells and RNA silencing have emerged as areas of intense interest for both basic and clinical research. Recently these fields have converged with reports implicating small regulatory RNAs in the maintenance and pluripotency of stem cells.
Stadler, Bradford M.; Ruohola-Baker, Hannele
Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors. This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues. Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair. This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS.
Drago, Denise; Cossetti, Chiara; Iraci, Nunzio; Gaude, Edoardo; Musco, Giovanna; Bachi, Angela; Pluchino, Stefano
Over the past decade, it has become increasingly clear that many tissues have regenerative capabilities. The challenge has been to find the stem cells or progenitors that are responsible for tissue renewal and repair. The revolution in technological advances that permit sophisticated spatial, temporal and kinetic analyses of stem cells has allowed stem cell hunters to ferret out where stem cells live, and to monitor when they come and go from these hiding places. PMID:21540847
Fuchs, Elaine; Horsley, Valerie
ABSTRACT: The remarkable speed with which the field of stem cell biology has evolved is unprecedented and has already changed the way we do science. In this series of articles we have invited leading experts to present their efforts in moving from the bench to the bedside, with the hope that we can learn from the experiences of the pioneers. PMID:22776286
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
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
Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.
Pluchino, Stefano; Cossetti, Chiara
Stem cells are multipotent, undifferentiated cells capable of multiplication and differentiation. Preliminary experimental evidence suggests that stem cells derived from embryonic or adult tissues (especially bone marrow) may develop into myocardial cells. Some experts believe that this phenomenon occurs naturally in human beings, specifically during recovery from a myocardial infarction. Recently, stem cells have been used with the therapeutic intention of regenerating damaged tissues. Cardiac experiments, mainly with adult homologous stem cells, have proved that this therapy is safe and may improve myocardial vascularization and pump function. We review current fundamental concepts regarding the normal development of embryonic stem cells into myocardial tissue and the heart as a whole. We describe the multiple conditions that naturally enable a stem cell to become a myocardial cell and a group of stem cells to become a heart. We also discuss the challenge of translating basic cellular and molecular mechanisms into effective, clinically relevant treatment options.
Angelini, Paolo; Markwald, Roger R.
Stems cells are defined as those cells which can divide to produce a daughter like themselves (self-renewal) as well as a daughter that will give rise to specific differentiated cells. Stem cells in the body may be unipotent, like spermatogenic stem cells (which are responsible for the continuing production of spermatozoa), or they can be multipotent, like neural or hemopoietic stem cells, which give rise respectively to all the varied cell types in the nervous system or in the blood and immune system. Given the possibility of directed differentiation of stem cells, these multipotent somatic stem cell lines may prove to be of significant clinical value. This article discusses the potential as well as the ethical issues associated with the use of stem cells.
Anne McLaren (Wellcome Trust/Cancer Research UK Gurdon Institute;)
Summary Glycans cover all cellular surfaces and, not surprisingly, are involved in many facets of stem cell biology and technology. For instance, coaxing stem cells to either proliferate or differentiate into the specific cell types needed for transplantation requires intricate glycan-dependent modulation of signalling molecules such as FGF-2, Wnt and Notch. Moreover, due to their prominent cell-surface localization and lineage-specific signatures, glycan epitopes such as the stage-specific embryonic antigens (Lewis X/SSEA-1, SSEA3–4) and tumor-rejection antigens (TRA1–60, 1–81) are ideally suited for identifying and isolating specific cell types from heterogeneous populations. Finally, the non-human sialic acid Neu5Gc has been detected on the surface of human embryonic stem cells due to metabolic incorporation from animal products used for their culture. Transplantation of Neu5Gc-contaminated cells poses immunological risks due to the presence, in humans, of circulating antibodies recognizing this glycan epitope.
Lanctot, Pascal M.; Gage, Fred H.; Varki, Ajit P.
The discovery that embryonic stem cells, neural stem cells and potentially mesenchymal stem cells bear the potential to differentiate into neurons and glia in vitro and in vivo has opened a rapidly growing scientific field. Current research is very likely to impose a major impact on diagnosis and treatment of a variety of neuropsychiatric disorders. One of the paramount immediate
Alexander Storch; Johannes Schwarz
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
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
Use of embryonic stem cells in research has been hotly debated for several years. This animation presents the basics on how stem cell lines are established. This animation from Cold Spring Harbor Laboratory's Dolan DNA Learning Center presents how embryonic stem cell lines are made through a series of illustrations of the processes involved.
The identification and characterization of stem cells for various tissues has led to a greater understanding of development, tissue maintenance, and cancer pathology. Stem cells possess the ability to divide throughout their life and to produce differentiated daughter cells while maintaining a population of undifferentiated cells that remain in the stem cell niche and that retain stem cell identity. Many cancers also have small populations of cells with stem cell characteristics. These cells have been called cancer stem cells and are a likely cause of relapse in cancer patients. Understanding the biology of stem cells and cancer stem cells offers great promise in the fields of regenerative medicine and cancer treatment. microRNAs (miRNAs) are emerging as important regulators of post-transcriptional gene expression and are considered crucial for proper stem cell maintenance and function. miRNAs have also been strongly implicated in the development and pathology of cancer. In this review, we discuss the characteristics of various stem cell types, including cancer stem cells, and the importance of miRNAs therein.
Hatfield, Steven; Ruohola-Baker, Hannele
Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in
Shane R. Mayack; Jennifer L. Shadrach; Francis S. Kim; Amy J. Wagers
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
Representing a renewable source for cell replacement, neural stem cells have received substantial attention in recent years. The neurosphere assay represents a method to detect the presence of neural stem cells, however owing to a deficiency of specific and definitive markers to identify them, their quantification and the rate they expand is still indefinite. Here we propose a mathematical interpretation
Loic P. Deleyrolle; Geoffery Ericksson; Brian J. Morrison; J. Alejandro Lopez; Kevin Burrage; Pamela Burrage; Angelo Vescovi; Rodney L. Rietze; Brent A. Reynolds; Mike O. Karl
Induced pluripotent stem (iPS) cells are an attractive source for potential cell-replacement therapy. However, transplantation of differentiated products harbors the risk of teratoma formation, presenting a serious health risk. Thus, we characterized Nanog-expressing (undifferentiated) cells remaining after induction of differentiation by cytological examination. To induce differentiation of iPS cells, we generated embryoid bodies (EBs) derived from iPS cells carrying a Nanog–green fluorescent protein(GFP) reporter and then injected GFP-positive and GFP negative EBs into nude mice. GFP-positive EB transplantation resulted in the formation of immature teratoma grade 3, but no tumors were induced by GFP-negative EB. GFP positive cells revealed significantly lower cytoplasmic area and higher nucleus/cytoplasm ratio than those of GFP negative cells. Our results suggest that morphological analysis might be a useful method for distinguishing between tumorigenic and nontumorigenic iPS cells. PMID:24122447
Nishimori, Makoto; Yakushiji, Hiromasa; Mori, Michihiro; Miyamoto, Tomoyuki; Yaguchi, Takahiro; Ohno, Setsuyo; Miyake, Yasuyuki; Sakaguchi, Takuya; Ueda, Masatsugu; Ohno, Eiji
Stem cells participate in dynamic physiologic systems that dictate the outcome of developmental events and organismal stress, Since these cells are fundamental to tissue maintenance and repair, the signals they receive play a critical role in the integrity of the organism. Much work has focused on stem cell identification and the molecular pathways involved in their regulation. Yet, we understand little about how these pathways achieve physiologically responsive stem cell functions. This chapter will review the state of our understanding of stem cells in the context of their microenvironment regarding the relation between stem cell niche dysfunction, carcinogenesis and aging.
Ferraro, Francesca; Celso, Cristina Lo; Scadden, David
Stem cells are fundamental units for achieving regenerative therapies, which leads naturally to a theoretical and experimental focus on these cells for therapeutic screening and intervention. A growing body of data in many tissue systems indicates that stem cell function is critically influenced by extrinsic signals derived from the microenvironment, or "niche." In this vein, the stem cell niche represents a significant, and largely untapped, entry point for therapeutic modulation of stem cell behavior. This Perspective will discuss how the niche influences stem cells in homeostasis, in the progression of degenerative and malignant diseases, and in therapeutic strategies for tissue repair. PMID:22482502
Wagers, Amy J
Voiding dysfunction comprises a variety of disorders, including stress urinary incontinence and overactive bladder, and affects millions of men and women worldwide. Erectile dysfunction (ED) also decreases quality of life for millions of men, as well as for their partners. Advanced age and diabetes are common comorbidities that can exacerbate and negatively impact upon the development of these disorders. Therapies that target the pathophysiology of these conditions to halt progression are not currently available. However, stem cell therapy could fill this therapeutic void. Stem cells can reduce inflammation, prevent fibrosis, promote angiogenesis, recruit endogenous progenitor cells, and differentiate to replace damaged cells. Adult multipotent stem cell therapy, in particular, has shown promise in case reports and preclinical animal studies. Stem cells have also enabled advances in urological tissue engineering by facilitating ex vivo construction of bladder wall and urethral tissue (using a patient's own cells) prior to transplantation. More recent studies have focused on bioactive factor secretion and homing of stem cells. In the future, clinicians are likely to utilize allogeneic stem cell sources, intravenous systemic delivery, and ex vivo cell enhancement to treat voiding dysfunction and ED.
Vaegler, Martin; Lenis, Andrew T; Daum, Lisa; Renninger, M; Bastian, Amend; Stenzl, Arnulf; Damaser, Margot S; Sievert, Karl-Dietrich
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
Several years ago, the discovery of a highly tumorigenic subpopulation of stem-like cells embedded within fresh surgical isolates of malignant gliomas lent support to a new paradigm in cancer biology--the cancer stem cell hypothesis. At the same time, these "glioma stem cells" seemed to resolve a long-standing conundrum on the cell of origin for primary cancers of the brain. However, central tenets of the cancer stem cell hypothesis have recently been challenged, and the cellular origins of stem-like cells within malignant glioma are still contended. Here, we summarize the issues that are still in play with respect to the cancer stem cell hypothesis, and we revisit the developmental origins of malignant glioma. Do glioma stem cells arise from developmentally stalled neural progenitors or from dedifferentiated astrocytes? Five separate predictions of a neural progenitor cell of origin are put to the test. PMID:18579075
Stiles, Charles D; Rowitch, David H
Stem cells in the body have a unique ability to renew themselves and give rise to more specialized cell types having functional commitments. Under specified growth conditions, these cell types remain unspecialized but can be triggered to become specific cell type of the body such as heart, nerve, or skin cells. This ability of embryonic stem cells for directed differentiation makes it a prominent candidate as a screening tool in revealing safer and better drugs. In addition, genetic variations and birth defects caused by mutations and teratogens affecting early human development could also be studied on this basis. Moreover, replacement of animal testing is needed because it involves ethical, legal, and cost issues. Thus, there is a strong requirement for validated and reliable, if achievable, human stem cell-based developmental assays for pharmacological and toxicological screening.
Tandon, S.; Jyoti, S.
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.
Shadrach, Jennifer L.; Wagers, Amy J.
Human stem cell studies are difficult because many of the powerful experimental approaches that mark and follow stem cells\\u000a and their progeny are impractical. Moreover, humans are long-lived, and it would literally take a lifetime to follow stem\\u000a cell fates prospectively. Considering these hurdles, an ideal method would not require prior experimental manipulations but\\u000a still allow “observations” of human stem
Darryl Shibata; Simon Tavaré
Stem cells have inherent tumor?trophic migratory properties and can serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease, making them promising anti?cancer agents. Encapsulation of therapeutically engineered stem cells in hydrogels has been utilized to provide a physical barrier to protect the cells from hostile extrinsic factors and significantly improve the therapeutic efficacy of transplanted stem cells in different models of cancer. This review aims to discuss the potential of different stem cell types for cancer therapy, various engineered stem cell based therapies for cancer, stem cell encapsulation process and provide an in depth overview of current applications of therapeutic stem cell encapsulation in the highly malignant brain tumor, glioblastoma multiforme (GBM), as well as the prospects for their clinical translation.
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.
Sun, Yubing; Weng, Shinuo
Stem cells are considered a valuable cellular resource for tissue replacement therapies in most brain disorders. Stem cells have the ability to self-replicate and differentiate into numerous cell types, including neurons, oligodendrocytes and astrocytes. As a result, stem cells have been considered the "holy grail" of modern medical neuroscience. Despite their tremendous therapeutic potential, little is known about the mechanisms that regulate their differentiation. In this review, we analyze stem cells in embryonic and adult brains, and illustrate the differentiation pathways that give origin to most brain cells. We also evaluate the emergent role of the well known anti-oxidant, vitamin C, in stem cell differentiation. We believe that a complete understanding of all molecular players, including vitamin C, in stem cell differentiation will positively impact on the use of stem cell transplantation for neurodegenerative diseases. PMID:23283434
Nualart, Francisco; Salazar, Katterine; Oyarce, Karina; Cisternas, Pedro; Jara, Nery; Silva-Álvarez, Carmen; Pastor, Patricia; Martínez, Fernando; García, Andrea; García-Robles, María de los Ángeles; Tapia, Juan Carlos
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
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 pluripotent stem cells have the potential to give rise to any cell type in the human body, but their therapeutic application remains challenging. The use of adult or tissue-restricted stem cells is emerging as another possible approach for the treatment of gastrointestinal diseases. The same self-renewal properties that allow stem cells to remain immortal and generate any tissue can occasionally make their proliferation difficult to control and make them susceptible to malignant transformation. This Review provides an overview of the different types of stem cell, focusing on tissue-restricted adult stem cells in the fields of gastroenterology and hepatology and summarizing the potential benefits and risks of using stems cells to treat gastroenterological and liver disorders.
Quante, Michael; Wang, Timothy C.
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
To overcome the difficulty of controlling stem cell fate and function in applications to regenerative medicine, a number of alternative approaches have been made. Recent reports demonstrate that a non-cellular niche modulating the biophysical microenvironment with chemical factors can support stem cell self-renewal. In our previous studies, early establishment was executed to optimize biophysical factors and it was subsequently found that the microgeometry of the extracellular matrix made huge differences in stem cell behavior and phenotype. We review here a three-dimensional, non-cellular niche designed to support stem cell self-renewal. The characteristics of stem cells under the designed system are further discussed.
Ahn, Ji Yeon; Lee, Seung Tae
New discoveries in stem cell biology are making the biology of solid tissues increasingly complex. Important seminal studies demonstrating the presence of damage-resistant cell populations together with new isolation and characterization techniques suggest that stem cells exist in the adult lung. More detailed in vivo molecular and cellular characterization of bronchioalveolar stem cells (BASCs), other putative lung stem and progenitor cells, and differentiated cells is needed to determine the lineage relationships in adult lung. Lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease, as well as the most common form of lung cancer in the United States, all involve apparent bronchiolar and alveolar cell defects. It is likely that the delicate balance of stem, progenitor, and differentiated cell functions in the lung is critically affected in patients with these devastating diseases. Thus the discovery of BASCs and other putative lung stem cells will lay the foundation for new inroads to understanding lung biology related to lung disease. PMID:17693488
Kim, Carla F
Rare cells with adult stem cell activity were recently discovered in human endometrium. Endometrial stem/progenitor cell candidates include epithelial, mesenchymal and endothelial cells, and all may contribute to the rapid endometrial regeneration following menstruation, rather than a single candidate. Endometrial mesenchymal stem-like cells (eMSC) are prospectively isolated as CD146(+)PDGF-R?(+) cells and are found in both basalis and functionalis as perivascular cells. Epithelial progenitor cells are detected in colony forming unit assays but their identity awaits elucidation. They are postulated to reside in the basalis in gland bases. Endometrial stem/progenitor cells may be derived from endogenous stem cells, but emerging evidence suggests a bone marrow contribution. Endometrial endothelial progenitor cells are detected as side population cells, which express several endothelial cell markers and differentiate into endometrial glandular epithelial, stromal and endothelial cells. Investigating endometrial stem cell biology is crucial to understanding normal endometrial physiology and to determine their roles in endometrial proliferative diseases. The nature of endometriosis suggests that initiation of ectopic endometrial lesions involves endometrial stem/progenitor cells, a notion compatible with Sampson's retrograde menstruation theory and supported by the demonstration of eMSC in menstrual blood. Evidence of cancer stem cells (CSC) in endometrial cancer indicates that new avenues for developing therapeutic options targeting CSC may become available. We provide an overview of the accumulating evidence for endometrial stem/progenitor cells and their possible roles in endometrial proliferative disorders, and discuss the unresolved issues. PMID:20627991
Gargett, Caroline E; Masuda, Hirotaka
The field of stem cell biology and regenerative medicine is rapidly moving toward translation to clinical practice, and in doing so has become even more dependent on animal donors and hosts for generating cellular reagents and assaying their potential therapeutic efficacy in models of human disease. Advances in cell culture technologies have revealed a remarkable plasticity of stem cells from embryonic and adult tissues, and transplantation models are now needed to test the ability of these cells to protect at-risk cells and replace cells lost to injury or disease. With such a mandate, issues related to acceptable sources and controversial (e.g., chimeric) models have challenged the field to provide justification of their potential efficacy before the passage of new restrictions that may curb anticipated breakthroughs. Progress from the use of both in vitro and in vivo regenerative medicine models already offers hope both for the facilitation of stem cell phenotyping in recursive gene expression profile models and for the use of stem cells as powerful new therapeutic reagents for cancer, stroke, Parkinson's, and other challenging human diseases that result in movement disorders. This article describes research in support of the following three objectives: (1) To discover the best stem or progenitor cell in vitro protocols for isolating, expanding, and priming these cells to facilitate their massive propagation into just the right type of neuronal precursor cell for protection or replacement protocols for brain injury or disease, including those that affect movement such as Parkinson's disease and stroke; (2) To discover biogenic factors--compounds that affect stem/progenitor cells (e.g., from high-throughput screening and other bioassay approaches)--that will encourage reactive cell genesis, survival, selected differentiation, and restoration of connectivity in central nervous system movement and other disorders; and (3) To establish the best animal models of human disease and injury, using both small and large animals, for testing new regenerative medicine therapeutics. PMID:17712220
Steindler, Dennis A
Stem cells are "big business" throughout medical technology, and their potential application in cosmetic procedures is no exception. One of the latest nonsurgical facial treatments (and new catchphrases) in plastic surgery is the "stem cell facelift." It is evident from the currently available scientific literature that the use of stem cell therapy for facial rejuvenation is limited to the theoretical induction of skin tightening and can in no way be equated to a facelift. In fact, what is advertised and promoted as a new and original technique of stem cell facelifting is mostly stem cell-enriched lipofilling. Despite encouraging data suggesting that adult stem cells hold promise for future applications, the data from clinical evidence available today do not substantiate the marketing and promotional claims being made to patients. To claim that the "stem cell facelift" is a complete facial rejuvenation procedure surgery is unethical. PMID:23417722
Atiyeh, Bishara S; Ibrahim, Amir E; Saad, Dibo A
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
Stem cells play a critical role in development and in tissue regeneration. The dental pulp contains a small sub-population of stem cells that are involved in the response of the pulp to caries progression. Specifically, stem cells replace odontoblasts that have undergone cell death as a consequence of the cariogenic challenge. Stem cells also secrete factors that have the potential to enhance pulp vascularization and provide the oxygen and nutrients required for the dentinogenic response that is typically observed in teeth with deep caries. However, the same angiogenic factors that are required for dentin regeneration may ultimately contribute to the demise of the pulp by enhancing vascular permeability and interstitial pressure. Recent studies focused on the biology of dental pulp stem cells revealed that the multipotency and angiogenic capacity of these cells could be exploited therapeutically in dental pulp tissue engineering. Collectively, these findings suggest new treatment paradigms in the field of Endodontics. The goal of this review is to discuss the potential impact of dental pulp stem cells to Regenerative Endodontics.
Rosa, Vinicius; Botero, Tatiana M.; Nor, Jacques E.
The capacity of pluripotency and self-renewal of human embryonic stem (hES) cells may provide unlimited cell source for cell replacement therapy. In this manuscript we summarize hES differentiation protocols coculture with PA6 or MS5 stromal cells. After 7? 9 days of differentiation, neural rosettes were robustly appeared followed by coculture with sonic hedgehog over-expressing stromal cells efficiently generated dopaminergic neural precursor cells. Using this protocol, the majority of differentiated hES cells contained nestin positive cells (?95%) and after final differentiation a high percentage of TuJ1 positive neurons was tyrosine hydroxylase positive (?40%).
Kim, Yong-Sik; Park, Chang-Hwan
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.
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
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
Nowadays, the cancer stem cells are considered to be significantly responsible for growth, metastasis, invasion and recurrence of all cancer. Cancer stem cells are typically characterized by continuous proliferation and self-renewal as well as by differentiation potential, while stem cells are considered to differentiate into tissue- specific phenotype of mature cells under the influence of micro-environment. Cancer stem cells should be traced to the stem cells under the influence of a micro-environment, which induces malignant tumors. In this review, we propose this micro-environment as a ‘cancerous niche’ and discuss its importance on the formation and maintenance of cancer stem cells with the recent experimental results to establish cancer stem cell models from induced pluripotent stem cells. These models of cancer stem cell will provide the great advantages in cancer research and its therapeutic applications in the future.
Kasai, T; Chen, L; Mizutani, AZ; Kudoh, T; Murakami, H; Fu, L; Seno, M
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
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
Hierarchical cell state models, wherein a few stem-like tumor-propagating cells repopulate the tumor after therapy, are often invoked in cancer. Suvŕ et al. demonstrate a plastic developmental hierarchy in glioma cell populations by characterizing the epigenetic states of phenotypically distinct cells and identifying four factors sufficient to reprogram differentiated cells into a tumorigenic stem-like state. PMID:24766799
Gronych, Jan; Pfister, Stefan M; Jones, David T W
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...
In this activity, learners play a game that models what happens as stem cells differentiate into different cell types. As learners play, they'll discover that a wide variety of cells can arise as different "cell fate decisions" are made along a stem cell's developmental path.
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 can…
Hurlbut, J. Benjamin; Robert, Jason Scott
Cell therapy is one of the most exciting fields in translational medicine. It stands at the intersection of a variety of rapidly developing scientific disciplines: stem cell biology, immunology, tissue engineering, molecular biology, biomaterials, transplantation biology, regenerative medicine, and clinical research. Cell-based therapy may develop into a new therapeutic platform to treat a vast array of clinical disorders. Blood transfusions and bone marrow transplantation are prime examples of the successful application of cell-based therapeutics; but recent advances in cellular and molecular biology have expanded the potential applications of this approach. Although recombinant genetic engineering to produce a variety of therapeutics such as human erythropoietin and insulin has proven successful, these treatments are unable to completely correct or reverse disease states, because most common disease processes are not due to the deficiency of a single protein but develop due to alterations in the complex interactions of a variety of cell components. In these complex situations, cell-based therapy may be a more successful strategy by providing a dynamic, interactive, and individualized therapeutic approach that responds to the pathophysiological condition of the patient. In this regard, cells may provide innovative methods for drug delivery of biologics, immunotherapy, and tissue regenerative or replacement engineering (1,2). The translation of this discipline to medical practice has tremendous potential, but in many applications technological issues need to be overcome. Since many cell-based indications are already being evaluated in the clinic, the field appears to be on the threshold of a number of successes. This review will focus on our group's use of human stem/progenitor cells in the treatment of acute and chronic renal failure as extensions to the current successful renal substitution processes of hemodialysis and hemofiltration.
Humes, H. David
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 unspecialized cells that can self renew indefinitely and differentiate into several somatic cells given the correct environmental cues. In the stem cell niche, stem cell-extracellular matrix (ECM) interactions are crucial for different cellular functions, such as adhesion, proliferation, and differentiation. Recently, in addition to chemical surface modifications, the importance of nanometric scale surface topography and roughness of biomaterials has increasingly becoming recognized as a crucial factor for cell survival and host tissue acceptance in synthetic ECMs. This review describes the influence of nanotopography on stem cell phenotypes.
Ravichandran, Rajeswari; Liao, Susan; Ng, Clarisse CH; Chan, Casey K; Raghunath, Michael; Ramakrishna, Seeram
\\u000a The acceptance of the Cancer Stem Cell (CSC) concept has revolutionized all aspects of our understanding of cancer biology,\\u000a from the cellular origin of cancer to its growth and expansion, shedding new light into the interrelations of all the cellular\\u000a components of the tumour and their role in its progression. From the therapeutic point of view, the existence of CSCs
A. Sagrera; J. Pérez-Losada; M. Pérez-Caro; R. Jiménez; I. Sánchez-García; C. Cobaleda
Adult mammalian skin consists of the epidermis, hair follicles (HFs), and sebaceous glands (SGs). Each of these three epithelial\\u000a lineages contains its own stem cell (SC) population for normal tissue homeostasis, HF cycling, and repair of the epidermis\\u000a following injury. Here, we provide an overview of the current knowledge on follicle SCs of the adult skin, including their\\u000a essential features
Leilei Yang; Ruiyun Peng
Gliomas are the most common tumours of the central nervous system (CNS) and a frequent cause of mental impairment and death.\\u000a Treatment of malignant gliomas is often palliative because of their infiltrating nature and high recurrence. Genetic events\\u000a that lead to brain tumours are mostly unknown. A growing body of evidence suggests that gliomas may rise from cancer stem\\u000a cells
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
Stem-cell-based therapies hold promise and potential to address many unmet clinical needs. Cell tracking with modern imaging modalities offers insight into the underlying biological process of the stem-cell-based therapies, with the goal to reveal cell survival, migration, homing, engraftment, differentiation, and functions. Adaptability, sensitivity, resolution, and non-invasiveness have contributed to the longstanding use of optical imaging for stem cell tracking and analysis. To identify transplanted stem cells from the host tissue, optically active probes are usually used to label stem cells before the administration. In comparison to the traditional fluorescent probes like fluorescent proteins and dyes, nanoparticle-based probes are advantageous in terms of the photo-stabilities and minimal changes to the cell phenotype. The main focus here is to overview the recent development of optically active nanoparticles for stem cells tracking. The related optical imaging modalities include fluorescence imaging, photoacoustic imaging, Raman and surface enhanced Raman spectroscopy imaging.
Gao, Yu; Cui, Yan; Chan, Jerry KY; Xu, Chenjie
An emerging concept in cancer biology is that a rare population of cancer stem cells exists among the heterogeneous cell mass that constitutes a tumor. This concept is best understood in human myeloid leukemia. Normal and malignant hematopoietic stem cell functions are defined by a common set of critical stemness genes that regulate self-renewal and developmental pathways. Several stemness factors, such as Notch or telomerase, show differential activation in normal hematopoietic versus leukemia stem cells. These differences could be exploited therapeutically even with drugs that are already in clinical use for the treatment of leukemia. The translation of novel and existing leukemic stem cell – directed therapies into clinical practice, however, will require changes in clinical trial design and the inclusion of stem cell biomarkers as correlative end points.
Chumsri, Saranya; Matsui, William; Burger, Angelika M.
Cell replacement and restorative therapies have great perspectives in the treatment of various diseases and traumas. Various types of stem cells, most different in the biological properties, are evaluated as the potential substrates of cell therapy for such diseases. Mesenchymal stem cells (MSC) posses relatively high proliferative activity and high level of plasticity, and can be differentiated not only to the cells of the mesenchymal lineage, but also to the neurons. Among the MSC populations, a population of endometrial stem cells, including that present in the menstrual blood, is available most readily. In the current study, we analyze biological properties of the menstrual blood stem cells and evaluate those cells as a potential substrate of cell therapy. PMID:23662573
Anisimova, S V; Zemel'ko, V I; Grinchuk, T M; Nikol'ski?, N N
Stem cells are defined by their ability to self-renew and their multi-potent differentiation capacity. As such, stem cells maintain tissue homeostasis throughout the life of a multicellular organism. Aerobic metabolism, while enabling efficient energy production, also generates reactive oxygen species (ROS), which damage cellular components. Until recently, the focus in stem cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer, and various anti-oxidative and anti-stress mechanisms of stem cells have been characterized. However, it has become increasingly clear that, in some cases, redox status plays an important role in stem cell maintenance, i.e., regulation of the cell cycle. An active area of current research is redox regulation in various cancer stem cells, the malignant counterparts of normal stem cells that are viewed as good targets of cancer therapy. In contrast to cancer cells, in which ROS levels are increased, some cancer stem cells maintain low ROS levels, exhibiting redox patterns that are similar to the corresponding normal stem cell. To fully elucidate the mechanisms involved in stem cell maintenance and to effectively target cancer stem cells, it is essential to understand ROS regulatory mechanisms in these different cell types. Here, the mechanisms of redox regulation in normal stem cells, cancer cells, and cancer stem cells are reviewed. PMID:21448925
Kobayashi, Chiharu I; Suda, Toshio
Knee meniscus, a fibrocartilaginous tissue, is characterized by heterogeneity in extracellular matrix (ECM) and biomechanical properties, and critical for orthopedic stability, load transmission, shock absorption, and stress distribution within the knee joint. Most damage to the meniscus cannot be effectively healed by the body due to its partial avascular nature; thus, damage caused by injury or age impairs normal knee function, predisposing patients to osteoarthritis. Meniscus tissue engineering offers a possible solution to this problem by generating replacement tissue that may be implanted into the defect site to mimic the function of natural meniscal tissue. To address this need, a multiporous, multilamellar meniscus was formed using silk protein scaffolds and stem cells. The silk scaffolds were seeded with human bone marrow stem cells and differentiated over time in chondrogenic culture in the presence of transforming growth factor-beta 3 to generate meniscus-like tissue in vitro. High cellularity along with abundant ECM leading to enhanced biomechanics similar to native tissue was found. Higher levels of collagen type I and II, sulfated glycosaminoglycans along with enhanced collagen 1-?1, aggrecan, and SOX9 gene expression further confirmed differentiation and matured cell phenotype. The results of this study are a step forward toward biomechanically competent meniscus engineering, reconstituting both form and function of the native meniscus.
Mandal, Biman B.; Park, Sang-Hyug; Gil, Eun Seok
Stem cells (SCs) are the key to tissue genesis and regeneration. Given their central role in homeostasis, dysfunctions of the SC compartment play a pivotal role in the development of cancers, degenerative disorders, chronic inflammatory pathologies and organ failure. The gastrointestinal tract is constantly exposed to harsh mechanical and chemical conditions and most of the epithelial cells are replaced every 3 to 5 d. According to the so-called Unitarian hypothesis, this renewal is driven by a common intestinal stem cell (ISC) residing within the crypt base at the origin of the crypt-to-villus hierarchical migratory pattern. Celiac disease (CD) can be defined as a chronic immune-mediated disease that is triggered and maintained by dietary proteins (gluten) in genetically predisposed individuals. Many advances have been achieved over the last years in understanding of the pathogenic interactions among genetic, immunological and environmental factors in CD, with a particular emphasis on intestinal barrier and gut microbiota. Conversely, little is known about ISC modulation and deregulation in active celiac disease and upon a gluten-free diet. Nonetheless, bone marrow-derived SC transplantation has become an option for celiac patients with complicated or refractory disease. This manuscript summarizes the “state of the art” regarding CD and ISCs, their niche and potential role in the development and treatment of the disease.
Piscaglia, Anna Chiara
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
Cytomegalovirus (CMV) infection causes high morbidity and mortality among allogeneic stem cell transplant recipients. Preemptive therapy with oral valganciclovir or intravenous ganciclovir has replaced universal prophylaxis. We prospectively studied 19 consecutive adult recipients of allogeneic peripheral blood stem cell transplants from May 2005 through February 2007 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV
F. de la Cruz-Vicente; P. Cerezuela Martinez; E. Gil-Espárraga; C. Martin Aguilera; M. Aguilar Guisado; R. Parody Ruiz-Berdejo; J. M. Cisneros Herreros; A. Urbano-Ispizua; I. Espigado Tocino
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
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.
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
Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases.
Unlike mouse embryonic stem cells (ESCs), which are closely related to the inner cell mass, human ESCs appear to be more closely related to the later primitive ectoderm. For example, human ESCs and primitive ectoderm share a common epithelial morphology, growth factor requirements, and the potential to differentiate to all three embryonic germ layers. However, it has previously been shown that human ESCs can also differentiate to cells expressing markers of trophoblast, an extraembryonic lineage formed before the formation of primitive ectoderm. Here, we show that phorbol ester 12-O-tetradecanoylphorbol 13-acetate causes human ESCs to undergo an epithelial mesenchymal transition and to differentiate into cells expressing markers of parietal endoderm, another extraembryonic lineage. We further confirmed that this differentiation is through the activation of protein kinase C (PKC) pathway and demonstrated that a particular PKC subtype, PKC-?, is most responsible for this transition.
Feng, Xuezhu; Zhang, Jiuchun; Smuga-Otto, Kimberly; Tian, Shulan; Yu, Junying; Stewart, Ron; Thomson, James A.
Tendon healing is fraught with complications such as reruptures and adhesion formation due to the formation of scar tissue at the injury site as opposed to the regeneration of native tissue. Stem cells are an attractive option in developing cell-based therapies to improve tendon healing. However, several questions remain to be answered before stem cells can be used clinically. Specifically, the type of stem cell, the amount of cells, and the proper combination of growth factors or mechanical stimuli to induce differentiation all remain to be seen. This paper outlines the current literature on the use of stem cells for tendon augmentation.
Gulotta, Lawrence V.; Chaudhury, Salma; Wiznia, Daniel
Anti-angiogenic pigment epithelium-derived factor (PEDF) is a multifunctional 50kD secreted glycoprotein emerging as a key factor in stem cell renewal. Characteristics of the stem cell niche can be highly dependent on location, access to the vasculature, oxygen tension and neighboring cells. In the neural stem cell (NSC) niche, specifically the subventricular zone, PEDF actively participates in the self renewal process and promotes stemness by upregulating Notch signaling effectors Hes1 and Hes5. The local vascular endothelial cells and ependymal cells are the likely sources of PEDF for the NSC while mesenchymal and retinal stem cells can actually produce PEDF. The opposing actions of PEDF and VEGF on various cells are recapitulated in the NSC niche. Intraventricular injection of PEDF promotes stem cell renewal, while injection of VEGF prompts differentiation and neurogenesis in the subventricular zone. Enhancing the expression of PEDF in stem cells has promising therapeutic implications. Bone marrow mesenchymal stem cells overexpressing PEDF effectively inhibited pathologic angiogenesis in the murine eye and these same cells suppressed hepatocellular carcinoma growth. As a protein with bioactivities in nearly all normal organ systems, it is likely that PEDF will continue to gain visibility as an essential component in the development and delivery of novel stem cell-based therapies to combat disease. PMID:23517628
Fitchev, Philip; Chung, Chuhan; Plunkett, Beth A; Brendler, Charles B; Crawford, Susan E
In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration. PMID:22926467
Rodríguez-Lozano, Francisco-Javier; Insausti, Carmen-Luisa; Iniesta, Francisca; Blanquer, Miguel; Ramírez, María-del-Carmen; Meseguer, Luis; Meseguer-Henarejos, Ana-Belén; Marín, Noemí; Martínez, Salvador; Moraleda, José-María
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
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
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by a progressive and extensive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and their terminals in the striatum, which results in debilitating movement disorders. This devastating disease affects over 1 million individuals in the United States and is increasing in incidence worldwide. Currently available pharmacological and surgical therapies ameliorate clinical symptoms in the early stages of disease, but they cannot stop or reverse degeneration of DA neurons. Stem cell therapies have come to the forefront of the PD research field as promising regenerative therapies. The majority of preclinical stem cell studies in experimental models of PD are focused on the idea that stem cell-derived DA neurons could be developed for replacement of diseased neurons. Alternatively, our studies and the studies from other groups suggest that stem cells also have the potential to protect and stimulate regeneration of compromised DA neurons. This review is focused on strategies based on the therapeutic potential for PD of the neurotrophic and neuroregenerative properties of a subclass of stem cells, mesenchymal stem cells (MSCs). PMID:23542820
Glavaski-Joksimovic, Aleksandra; Bohn, Martha C
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
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
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
First created in 2006 from adult somatic cells by a simple molecular genetic trick, induced pluripotent stem cells (iPS) system is the latest platform in stem cell research. Induced pluripotent stem cells are produced by nuclear reprogramming technology and they resemble embryonic stem cells (ES) in key elements; they possess the potentiality to differentiate into any type of cell in the body. More importantly, the iPS platform has distinct advantage over ES system in the sense that iPS-derived cells are autologous and therefore the iPS-derived transplantation does not require immunosuppressive therapy. In addition, iPS research obviates the political and ethical quandary associated with embryo destruction and ES research. This remarkable discovery of cellular plasticity has important medical implications. This brief review summarizes currently available stem cell platforms, with emphasis on cellular reprogramming and iPS technology and its application in disease modeling and cell replacement therapy in neurodegenerative diseases. PMID:21891933
Verma, Ashok; Verma, Nipun
The stem-cement interface experiences fretting wear in vivo due to low-amplitude oscillatory micromotion under physiological loading, as a consequence it is considered to play an important part in the overall wear of cemented total hip replacement. Despite its potential significance, in-vitro simulation to reproduce fretting wear has seldom been attempted and even then with only limited success. In the present study, fretting wear was successfully reproduced at the stem-cement interface through an in-vitro wear simulation, which was performed in part with reference to ISO 7206-4: 2002. The wear locations compared well with the results of retrieval studies. There was no evidence of bone cement transfer films on the stem surface and no fatigue cracks in the cement mantle. The cement surface was severely damaged in those areas in contact with the fretting zones on the stem surface, with retention of cement debris in the micropores. Furthermore, it was suggested that these micropores contributed to initiation and propagation of fretting wear. This study gave scope for further comparative study of the influence of stem geometry, stem surface finish, and bone cement brand on generation of fretting wear. PMID:18161257
Brown, L; Zhang, H; Blunt, L; Barrans, S
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
The skin is the first line of defense against dehydration and external environmental aggressions. It constantly renews itself throughout adult life mainly due to the activity of tissue-specific stem cells. In this review, we discuss fundamental characteristics of different stem cell populations within the skin and how they are able to contribute to normal skin homeostasis. We also examine the most recent results regarding the cell-intrinsic and -extrinsic components of the stem cell niche within the adult skin epithelium. Finally, we address the recent efforts to understand how abnormal regulation of stem cell activity contributes to the initiation and progression of skin-associated cancers. PMID:24439804
Tadeu, Ana Mafalda Baptista; Horsley, Valerie
Recombinant rat stem cell factor (SCF) has been shown to decrease lethality in mice exposed to total-body irradiation (TBI) in the lower range of lethality through radioprotection of hematopoietic stem cells and acceleration of bone marrow repopulation. This study evaluates the effect of SCF on the survival of the intestinal mucosal stem cell after TBI. This non-hematopoietic cell is clinically
B. R. Leigh; W. Khan; S. L. Hancock
Highlights: Black-Right-Pointing-Pointer MSC like cells were derived from hESC by a simple and reproducible method. Black-Right-Pointing-Pointer Differentiation and immunosuppressive features of MSCl cells were similar to bmMSC. Black-Right-Pointing-Pointer MSCl cells as feeder cells support the undifferentiated growth of hESC. -- Abstract: Mesenchymal stem cell like (MSCl) cells were generated from human embryonic stem cells (hESC) through embryoid body formation, and isolated by adherence to plastic surface. MSCl cell lines could be propagated without changes in morphological or functional characteristics for more than 15 passages. These cells, as well as their fluorescent protein expressing stable derivatives, efficiently supported the growth of undifferentiated human embryonic stem cells as feeder cells. The MSCl cells did not express the embryonic (Oct4, Nanog, ABCG2, PODXL, or SSEA4), or hematopoietic (CD34, CD45, CD14, CD133, HLA-DR) stem cell markers, while were positive for the characteristic cell surface markers of MSCs (CD44, CD73, CD90, CD105). MSCl cells could be differentiated toward osteogenic, chondrogenic or adipogenic directions and exhibited significant inhibition of mitogen-activated lymphocyte proliferation, and thus presented immunosuppressive features. We suggest that cultured MSCl cells can properly model human MSCs and be applied as efficient feeders in hESC cultures.
Varga, Nora [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)] [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Vereb, Zoltan; Rajnavoelgyi, Eva [Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen (Hungary)] [Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen (Hungary); Nemet, Katalin; Uher, Ferenc; Sarkadi, Balazs [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)] [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Apati, Agota, E-mail: firstname.lastname@example.org [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)] [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)
If a surgeon is faced with altered lesser trochanter anatomy when revising the femoral component in revision total hip replacement, a peri-prosthetic fracture, or Paprosky type IIIb or type IV femoral bone loss, a modular tapered stem offers the advantages of accurately controlling femoral version and length. The splines of the taper allow rotational control, and improve the fit in femoral canals with diaphyseal bone loss. In general, two centimetres of diaphyseal contact is all that is needed to gain stability with modular tapered stems. By allowing the proximal body trial to rotate on a well-fixed distal segment during trial reduction, appropriate anteversion can be obtained in order to improve intra-operative stability, and decrease the dislocation risk. However, modular stems should not be used for all femoral revisions, as implant fracture and corrosion at modular junctions can still occur. PMID:24187363
Cross, M B; Paprosky, W G
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
For reasons that are unclear the production of embryonic stem cells from ungulates has proved elusive. Here, we describe induced pluripotent stem cells (iPSC) derived from porcine fetal fibroblasts by lentiviral transduction of 4 human (h) genes, hOCT4, hSOX2, hKLF4, and hc-MYC, the combination commonly used to create iPSC in mouse and human. Cells were cultured on irradiated mouse embryonic fibroblasts (MEF) and in medium supplemented with knockout serum replacement and FGF2. Compact colonies of alkaline phosphatase-positive cells emerged after approximately 22 days, providing an overall reprogramming efficiency of approximately 0.1%. The cells expressed porcine OCT4, NANOG, and SOX2 and had high telomerase activity, but also continued to express the 4 human transgenes. Unlike human ESC, the porcine iPSC (piPSC) were positive for SSEA-1, but negative for SSEA-3 and -4. Transcriptional profiling on Affymetrix (porcine) microarrays and real time RT-PCR supported the conclusion that reprogramming to pluripotency was complete. One cell line, ID6, had a normal karyotype, a cell doubling time of approximately 17 h, and has been maintained through >220 doublings. The ID6 line formed embryoid bodies, expressing genes representing all 3 germ layers when cultured under differentiating conditions, and teratomas containing tissues of ectoderm, mesoderm, and endoderm origin in nude mice. We conclude that porcine somatic cells can be reprogrammed to form piPSC. Such cell lines derived from individual animals could provide a means for testing the safety and efficacy of stem cell-derived tissue grafts when returned to the same pigs at a later age. PMID:19541600
Ezashi, Toshihiko; Telugu, Bhanu Prakash V L; Alexenko, Andrei P; Sachdev, Shrikesh; Sinha, Sunilima; Roberts, R Michael
Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypoperfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypoperfusion with symptology is reported. Mesenchymal stem cells (MSC) are in late phases of clinical development for treatment of graft versus host disease and Crohn's Disease, two conditions of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators, having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children receiving cord blood CD34+ cells. We propose the combined use of MSC and cord blood CD34+cells may be useful in the treatment of autism.
Ichim, Thomas E; Solano, Fabio; Glenn, Eduardo; Morales, Frank; Smith, Leonard; Zabrecky, George; Riordan, Neil H
The cancer stem cell (CSC) concept, which arose about a decade ago, proposes that tumor growth is sustained by a subpopulation of highly malignant cells. These cells, termed CSCs, are capable of extensive self-renewal that contributes to metastasis and treatment resistance. Therefore, therapeutic strategies that target CSCs should be developed for improving outcomes of cancer patients. Recent progress has highlighted the importance of physical properties of the extracellular matrix and mechanotransduction pathway in cancer cells during cancer development. On the other hand, the significance of CXCR1, an upstream signal of FAK/PI3K/Akt has been revealed in CSCs. FAK/PI3K/Akt is a key signal mediator in mechanotransduction pathway. Therefore, mechanotransduction could be a new target for CSCs, and would be an innovative way to treat cancer by inhibiting FAK/PI3K/Akt. PMID:23576457
Hao, Jin; Zhang, Yueling; Ye, Rui; Zheng, Yingcheng; Zhao, Zhihe; Li, Juan
Neurodegenerative diseases result from the gradual and progressive loss of neural cells and lead to nervous system dysfunction. The rapidly advancing stem cell field is providing attractive alternative options for fighting these diseases. Results have provided proof of principle that cell replacement can work in humans with Parkinson's disease (PD). However, three clinical studies of cell transplantation were published that found no net benefit, while patients in two of the studies developed dyskinesias that persisted despite reductions in treatment. Induced pluripotent stem cells (iPSC) have major potential advantages because patient-specific neuroblasts are suitable for transplantation, avoid immune reactions, and can be produced without the use of human ES cells (hESC). Although iPSCs have not been successfully used in clinical trials for PD, patients with amyotrophic lateral sclerosis (ALS) were treated with autologous stem cells and, though they had some degree of decline one year after treatment, they were still improved compared with the preoperative period or without any drug therapy. In addition, neural stem cells (NSCs), via brain-derived neurotrophic factor (BDNF), have been shown to ameliorate complex behavioral deficits associated with widespread Alzheimer's disease (AD) pathology in a transgenic mouse model of AD. So far, the FDA lists 18 clinical trials treating multiple sclerosis (MS), but most are in preliminary stages. This article serves as an overview of recent studies in stem cell and regenerative approaches to the above chronic neurodegenerative disorders. There are still many obstacles to the use of stem cells as a cure for neurodegenerative disease, especially because we still don't fully understand the true mechanisms of these diseases. However, there is hope in the potential of stem cells to help us learn and understand a great deal more about the mechanisms underlying these devastating neurodegenerative diseases. PMID:22070610
Feng, Zhongling; Gao, Feng
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
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
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.
Zhang, Qiucen; Austin, Robert H.
A variety of human and animal stem cells (rat and human adult pancreatic stem cells, salivary gland stem cells, dental pulpa stem cells) have been investigated by femtosecond laser 5D two-photon microscopy. Autofluorescence and second harmonic generation have been imaged with submicron spatial resolution, 270 ps temporal resolution, and 10 nm spectral resolution. In particular, NADH and flavoprotein fluorescence was detected in stem cells. Major emission peaks at 460nm and 530nm with typical mean fluorescence lifetimes of 1.8 ns and 2.0 ns, respectively, were measured using time-correlated single photon counting and spectral imaging. Differentiated stem cells produced the extracellular matrix protein collagen which was detected by SHG signals at 435 nm.
Uchugonova, A.; Gorjup, E.; Riemann, I.; Sauer, D.; König, K.
Stem cells are responsible for tissue repair and maintenance and it is assumed that changes observed in the stem cell compartment with age underlie the concomitant decline in tissue function. Studies in murine models have highlighted the importance of intrinsic changes occurring in stem cells with age. They have also drawn the attention to other factors, such as changes in the local or systemic environment as the primary cause of stem cell dysfunction. Whilst knowledge in murine models has been advancing rapidly there has been little translation of these data to human aging. This is most likely due to the difficulties of testing the regenerative capacity of human stem cells in vivo and to substantial differences in the aging phenotype within humans. Here we summarize evidence to show how progeroid syndromes, integrated with other models, can be valuable tools in addressing questions about the role of stem cell aging in human degenerative diseases of older age and the molecular pathways involved. PMID:21739188
Bellantuono, I; Sanguinetti, G; Keith, W N
Tooth loss or absence is a common condition that can be caused by various pathological circumstances. The replacement of the missing tooth is important for medical and aesthetic reasons. Recently, scientists focus on tooth tissue engineering, as a potential treatment, beyond the existing prosthetic methods. Tooth engineering is a promising new therapeutic approach that seeks to replace the missing tooth with a bioengineered one or to restore the damaged dental tissue. Its main tool is the stem cells that are seeded on the surface of biomaterials (scaffolds), in order to create a biocomplex. Several populations of mesenchymal stem cells are found in the tooth. These different cell types are categorized according to their location in the tooth and they demonstrate slightly different features. It appears that the dental stem cells isolated from the dental pulp and the periodontal ligament are the most powerful cells for tooth engineering. Additional research needs to be performed in order to address the problem of finding a suitable source of epithelial stem cells, which are important for the regeneration of the enamel. Nevertheless, the results of the existing studies are encouraging and strongly support the belief that tooth engineering can offer hope to people suffering from dental problems or tooth loss.
Lymperi, S; Ligoudistianou, C; Taraslia, V; Kontakiotis, E; Anastasiadou, E
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)
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
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
The last decade has witnessed the publication of a large number of clinical trials, primarily using bone marrow-derived stem cells as the injected cell. Much has been learned through these "first-generation" clinical trials. The considerable advances in our understanding include (1) cell therapy is safe, (2) cell therapy has been modestly effective, (3) the recognition that in humans bone marrow-derived stem cells do not transdifferentiate into cardiomyocytes or new blood vessels (or at least in sufficient numbers to have any effect). The primary mechanism of action for cell therapy is now believed to be through paracrine effects that include the release of cytokines, chemokines, and growth factors that inhibit apoptosis and fibrosis, enhance contractility, and activate endogenous regenerative mechanisms through endogenous circulating or site-specific stem cells. The new direction for clinical trials includes the use of stem cells capable of cardiac lineage, such as endogenous cardiac stem cells. PMID:24595173
Michler, Robert E
The last decade has witnessed the publication of a large number of clinical trials primarily using bone marrow-derived stem cells as the injected cell. These “first-generation” clinical trials have advanced our understanding and shown us that (1) cell therapy is safe, (2) cell therapy has been modestly effective, and (3) in humans, bone marrow-derived stem cells do not transdifferentiate into cardiomyocytes or new blood vessels (or at least in sufficient numbers to have any effect). The primary mechanism of action for cell therapy is now believed to be through paracrine effects that include the release of cytokines, chemokines, and growth factors that inhibit apoptosis and fibrosis, enhance contractility, and activate endogenous regenerative mechanisms through endogenous circulating or site-specific stem cells. The new direction for clinical trials includes the use of stem cells capable of cardiac lineage, such as endogenous cardiac stem cells.
Distinct stem cell types have been established from embryos and identified in the fetal tissues and umbilical cord blood as well as in specific niches in many adult mammalian tissues and organs such as bone marrow, brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, and prostate. All stem cells are undifferentiated cells that exhibit unlimited self-renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishing the cells or to tissue regeneration after injury. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of stem cells in the treatment of ophthalmic disorders. Experimental and human studies with intravitreal bone marrow-derived stem cells have begun. This paper reviews recent advances and potential sources of stem cells for cell therapy in retinal diseases.
Embryonic stem (ES) cells, derived from early stage embryos, are pluripotent precursors of all of the tissues and organs of the body. ES cells from the mouse have been shown to undergo differentiation in vitro to form a variety of different cell types, including the differentiated progeny of hematopoietic precursors. These hematopoietic cells, however, exhibit numerous differences from those of human cells, and it has become increasingly clear that mouse ES cell differentiation has significant limitations as a model of human developmental biology. The more recent isolation and characterization of nonhuman primate ES cell lines have made available an experimental model with characteristics considerably more close to human biology. We have developed experimental conditions that promote efficient differentiation of these cells to produce progeny cells with considerable similarity to hematopoietic precursors harvested from bone marrow of adult animals. PMID:17141039
Li, Fei; Lu, Shi-Jiang; Honig, George R
Human umbilical cord blood (UCB) is a valuable alternative source of ethically acceptable, clinically competent stem cells that is most likely closest to embryonic stem cells. Development of reliable methods for the expansion of cord blood stem cells is critical to ensure their clinical application. In the present article, advances in cord blood stem cell isolation, culture expansion methods through co-culture with human mesenchymal stem cells, culture optimization techniques with defined media and cord blood stem cell banking aspects have been reviewed. Refined methods of isolation as well as defined culture conditions of expansion that favor retention of stem cell phenotype and proper cryogenic storage can significantly increase the use of cord blood stem cells in human cell therapy applications. PMID:20232595
Gu, Yu-Chen; Rao, Mahendra S; Vemuri, Mohan C
Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored. PMID:24064536
Brafman, David A
Stem cells have drawn extraordinary attention from scientists and the general public due to their potential to generate effective therapies for incurable diseases. At the same time, the production of embryonic stem cells involves a serious ethical issue concerning the destruction of human embryos. Although adult stem cells and induced pluripotential cells do not pose this ethical objection, there are other bioethical challenges common to all types of stem cells related particularly to the clinical use of stem cells. Their clinical use should be based on clinical trials, and in special situations, medical innovation, both of which have particular ethical dimensions. The media has raised unfounded expectations in patients and the public about the real clinical benefits of stem cells. At the same time, the number of unregulated clinics is increasing around the world, making direct offers through Internet of unproven stem cell therapies that attract desperate patients that have not found solutions in standard medicine. This is what is called stem cells tourism. This article reviews this situation, its consequences and the need for international cooperation to establish effective regulations to prevent the exploitation of patients and to endanger the prestige of legitimate stem cell research. PMID:24448860
Ventura-Juncá, Patricio; Erices, Alejandro; Santos, Manuel J
Adult skeletal muscle stem cells are a heterogeneous cell population characterized by a small subset of undifferentiated cells that express at high level the paired/homeodomain gene Pax7. This category of satellite cells divides predominantly by asymmetric chromatid segregation generating a daughter cell that carries the mother DNA and retains stem cell property, and a daughter cell that inherits the newly-synthesized DNA and acquires the myocyte lineage.1
Anversa, Piero; Leri, Annarosa; Kajstura, Jan
Stem cell banks are increasingly seen as an essential resource of biological materials for both basic and translational research.\\u000a Stem cell banks support transnational access to quality-controlled and ethically sourced stem cell lines from different origins\\u000a and of varying grades. According to the Organisation for Economic Co-operation and Development, advances in regenerative medicine\\u000a are leading to the development of a
Bartha M Knoppers; Rosario Isasi
This article examines the assertion that human embryonic stem cells patents are immoral because they violate human dignity.\\u000a After analyzing the concept of human dignity and its role in bioethics debates, this article argues that patents on human\\u000a embryos or totipotent embryonic stem cells violate human dignity, but that patents on pluripotent or multipotent stem cells\\u000a do not. Since patents
David B. Resnik
Abstract Induced pluripotent stem cells (iPSCs) have potential applications in the restoration of fertility, regenerative medicine, and animal biotechnology. In this study, we present the induction of iPSCs from mouse Sertoli cells (SCs) by introducing four factors-Oct4, Sox2, Klf4, and c-Myc. As early as day 3 after induction, expression of these factors was detected and typical embryonic stem-like cells began to form. On day 18, these exogenous genes were silenced and colonies were selected according to morphological characteristics. The iPSCs induced from SCs, termed SCiPSCs, strongly expressed pluripotent markers, showed a normal karyotype, and had proliferation and differentiation characteristics similar to those of embryonic stem cells (ESCs), both in vitro and in vivo. Furthermore, exposure of SCiPSCs to nitric oxide (NO) allowed them to maintain pluripotency through the activation of the pluripotent genes Oct4 and Sox2 and upregulation of Nanog expression. Moreover, NO prevented SCiPSCs from undergoing apoptosis by activating the antiapoptotic genes Bcl2 and Bcl2lll, downregulating the proapoptotic genes Bak1 and Casp7, and blocking the activation of the proapoptotic gene Bac. These effects were reversed by exposure to l-NG-monomethylarginine (l-NMMA), a NO inhibitor. These data demonstrate that iPSCs can be generated from SCs and that the self-renewal and pluripotency of SCiPS cells can be maintained in the presence of NO. PMID:24802333
Sun, Hongyan; Zhang, Guomin; Dong, Fulu; Wang, Feng; Cao, Wenguang
The mathematical models prevalently used to represent stem cell proliferation do not have the level of accuracy that might be desired. The hyperbolastic growth models promise a greater degree of precision in representing data of stem cell proliferation. The hyperbolastic growth model H3 is applied to experimental data in both embryonic stem cells and adult mesenchymal stem cells. In the embryonic stem cells the results are compared with other popular models, including the Deasy model, which is used prevalently for stem cell growth. In the case of modelling adult mesenchymal stem cells, H3 is also successfully applied to describe the proliferative index. We demonstrated that H3 can accurately represent the dynamics of stem cell proliferation for both embryonic and adult mesenchymal stem cells. We also recognize the importance of additional factors, such as cytokines, in determining the rate of growth. We propose the question of how to extend H3 to a multivariable model that can include the influence of growth factors. PMID:20953843
Tabatabai, Mohammad A; Bursac, Zoran; Eby, Wayne M; Singh, Karan P
Human stem cell research may have many promising benefits, including giving us the ability to regenerate human tissue and organs, understand the process of early human development, and provide better models to test new drugs. However, it is very controversial and in many cases presently illegal because stem cells may be derived from human embryos or from a cloning process. This paper outlines the various techniques which may be used for deriving stem cells, the ethical problems such research presents, and suggestions for creating policy for human stem cells research. PMID:11936141
Superparamagnetic iron oxide (SPIO) nanoparticles are being used for intracellular magnetic labeling of stem cells and other cells in order to monitor cell trafficking by magnetic resonance imaging (MRI) as part of cellular-based repair, replacement and treatment strategies. This review focuses on the various methods for magnetic labeling of stem cells and other mammalian cells and on how to translate experimental results from bench to bedside. PMID:15773025
Frank, J A; Anderson, S A; Kalsih, H; Jordan, E K; Lewis, B K; Yocum, G T; Arbab, A S
Mesenchymal stem cells are a heterogeneous population of fibroblast-like stromal cells that have been isolated from the bone marrow and a number of organs and tissues including the kidney. They have multipotent and self-renewing properties and can differentiate into cells of the mesodermal lineage. Following their administration in vivo, mesenchymal stem cells migrate to damaged kidney tissue where they produce an array of anti-inflammatory cytokines and chemokines that can alter the course of injury. Mesenchymal stem cells are thought to elicit repair through paracrine and/or endocrine mechanisms that modulate the immune response resulting in tissue repair and cellular replacement. This review will discuss the features of mesenchymal stem cells and the factors they release that protect against kidney injury; the mechanisms of homing and engraftment to sites of inflammation; and further elucidate the immunomodulatory effect of mesenchymal stem cells and their ability to alter macrophage phenotype in a setting of kidney damage and repair. PMID:21777348
Wise, Andrea F; Ricardo, Sharon D
Over the last decade or so, intensive research in cardiac stem cell biology has led to significant discoveries towards a potential therapy for cardiovascular disease; the main cause of morbidity and mortality in humans. The major goal within the field of cardiovascular regenerative medicine is to replace lost or damaged cardiac muscle and coronaries following ischaemic disease. At present, de novo cardiomyocytes can be generated either in vitro, for cell transplantation or disease modelling using directed differentiation of embryonic stem cells or induced pluripotent stem cells, or in vivo via direct reprogramming of resident adult cardiac fibroblast or ectopic stimulation of resident cardiac stem or progenitor cells. A major bottleneck with all of these approaches is the low efficiency of cardiomyocyte differentiation alongside their relative functional immaturity. Chemical genetics, and the application of phenotypic screening with small molecule libraries, represent a means to enhance understanding of the molecular pathways controlling cardiovascular cell differentiation and, moreover, offer the potential for discovery of new drugs to invoke heart repair and regeneration. Here, we review the potential of chemical genetics in cardiac stem cell therapy, highlighting not only the major contributions to the field so far, but also the future challenges. LINKED ARTICLES This article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-2
Vieira, Joaquim M; Riley, Paul R
Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model
Chenwei Li; David G. Heidt; Piero Dalerba; Charles F. Burant; Lanjing Zhang; Volkan Adsay; Max Wicha; Michael F. Clarke; Diane M. Simeone
The NCI lentiviral plasmid can identify the putative cancer stem cell population through the expression of fluorescent or luminescent proteins and has the potential to advance new therapies. The key feature of the plasmid is a reporter system that only detects cells expressing the core stem cell transcription factors Sox2 and Oct4.
The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the
Tannishtha Reya; Hans Clevers
Wnt signaling has been implicated in the control over various types of stem cells and may act as a niche factor to maintain stem cells in a self-renewing state. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to ß-catenin, which then
Roel Nusse; W. Ching; K. Harnish; C. Logan; A. Zeng; D. ten Berge; Y. Kalani
Embryonic stem (ES) cells have been proposed as candidates for cell replacement therapy in patients with intestinal failure because these cells can be expanded indefinitely without losing their pluripotent phenotype. We investigated the differentiation capacity of mouse ES cells into gut-like structures, including intestinal stem cells, and defined culture conditions for efficient induction of formation of these structures. ES cell-derived gut-like structures (ES-guts) were reproducibly induced in developing embryoid bodies (EBs) by day 21 of differentiation culture. ES-guts contained an endodermal epithelium, a smooth muscle layer, interstitial cells of Cajal, and enteric neurons and showed spontaneous contraction. Transplantation of ES-guts under the kidney capsules of immunodeficient mice induced formation of highly differentiated epithelium composed of absorptive cells and goblet cells in the grafts. Immunoreactivity for Musashi-1 (Msi-1), a marker of intestinal stem cells, was detected in 1.9% of the columnar epithelial cells in the graft. Culture with 0.1% dimethyl sulfoxide increased the numbers of ES-guts in EBs, and serum-replacement (SR) culture, in comparison to standard ES culture containing 15% serum, increased the area ratio of ES-guts to EBs. SR culture also promoted maturation of epithelium to form a single layer of columnar epithelial cells, including absorptive cells and goblet cells. Expression of Msi-1 mRNA and protein was significantly enhanced when EBs were cultured under SR conditions. In conclusion, SR conditions efficiently induce formation of ES-guts and promote differentiation of epithelium, including intestinal stem cells. These results suggest the feasibility of cell-based therapy for intestinal failure based on ES cell culture systems. PMID:18680392
Konuma, Noriyoshi; Wakabayashi, Kumiko; Matsumoto, Taro; Kusumi, Yoshiaki; Masuko, Takayuki; Iribe, Yuji; Mitsumata, Masako; Okano, Hideyuki; Kusafuka, Takeshi; Mugishima, Hideo
Although improvements in conventional treatment have enhanced the prognosis of thalassaemia, stem cell transplantation remains the only cure. Over the last 2 decades, progress in preventive strategies, effective control of transplant related complications and development of new preparative regimens, have considerably improved the results of transplants from HLA-identical siblings. Currently class 1, class 2 and class 3 patients receiving bone marrow transplantation (BMT) from an HLA-identical related donor have 87, 85 and 80% of probability of thalassaemia-free survival. The results of transplant in adult patients treated with current protocols are less successful. This study reports experience with BMT for thalassaemia. PMID:15705305
Gaziev, Javid; Lucarelli, Guido
Embryonic stem cells (ESCs) are a powerful model for genetic engineering, studying developmental biology, and modeling disease. To date, ESCs have been established from the mouse (Evans and Kaufman, 1981, Nature 292:154-156), non-human primates (Thomson et al., , Proc Nat Acad Sci USA 92:7844-7848), humans (Thomson et al., 1998, Science 282:1145-1147), and rats (Buehr et al., , Cell 135:1287-1298); however, the derivation of ESCs from domesticated ungulates such as goats, sheep, cattle, and pigs have not been successful. Alternatively, induced pluripotent stem cells (iPSCs) can be generated by reprogramming somatic cells with several combinations of genes encoding transcription factors (OCT3/4, SOX2, KLF4, cMYC, LIN28, and NANOG). To date, iPSCs have been isolated from various species, but only limited information is available regarding goat iPSCs (Ren et al., 2011, Cell Res 21:849-853). The objectives of this study were to generate goat iPSCs from fetal goat primary ear fibroblasts using lentiviral transduction of four human transcription factors: OCT4, SOX2, KLF4, and cMYC. The goat iPSCs were successfully generated by co-culture with mitomycin C-treated mouse embryonic fibroblasts using medium supplemented with knockout serum replacement and human basic fibroblast growth factor. The goat iPSCs colonies are flat, compact, and closely resemble human iPSCs. They have a normal karyotype; stain positive for alkaline phosphatase, OCT4, and NANOG; express endogenous pluripotency genes (OCT4, SOX2, cMYC, and NANOG); and can spontaneously differentiate into three germ layers in vitro and in vivo. PMID:24123501
Song, Hui; Li, Hui; Huang, Mingrui; Xu, Dan; Gu, Chenghao; Wang, Ziyu; Dong, Fulu; Wang, Feng
Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumor development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumors and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse. Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective. This review will outline the recent discoveries for CSCs across the major tumor types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies and the outlook for the future development of this emerging area will be given.
Kousparou, Christina A; Epenetos, Agamemnon A
Nearly 12% of the population in the United States will be afflicted with a thyroid related disorder during their lifetime. Common treatment approaches are tailored to the specific disorder and include surgery, radioactive iodine ablation, antithyroid drugs, thyroid hormone replacement, external beam radiation, and chemotherapy. Regenerative medicine endeavors to combat disease by replacing or regenerating damaged, diseased, or dysfunctional body parts. A series of achievements in pluripotent stem cell research have transformed regenerative medicine in many ways by demonstrating “repair” of a number of body parts in mice, of which, the thyroid has now been inducted into this special group. Seminal work in pluripotent cells, namely embryonic stem cells and induced pluripotent stem cells, have made possible their path to becoming key tools and biological building blocks for cell-based regenerative medicine to combat the gamut of human diseases, including those affecting the thyroid.
Sewell, Will; Lin, Reigh-Yi
In this study, we examined 96 undergraduate non-science majors’ conceptions of stem cells, stem cell research, and cloning.\\u000a This study was performed at a large, Midwest, research extensive university. Participants in the study were asked to answer\\u000a 23 questions relating to stem cells, stem cell research, and cloning in an on-line assessment before and after instruction.\\u000a Two goals of the
James P. Concannon; Marcelle A. Siegel; Kristy Halverson; Sharyn Freyermuth
During human development, stem cells establish themselves in specific anatomic locations or niches. The niche harbors the stem cells, and regulates how stem cells proliferate. The interaction between stem cells and their niche affects stem cell function, and offers an opportunity to improve the marrow microenvironment. Osteoblasts produce hematopoietic growth factors and are activated by parathyroid hormone (PTH). A calcium
Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but
Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.
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 high priority for funding, and it appears clear that the evolving field of tissue engineering and regenerative medicine will require as its underpinning a thorough understanding of the molecular regulation of stem cell proliferation, differentiation, self-renewal, and aging. Despite evidence suggesting that embryonic stem (ES) cells might represent a more potent regenerative reservoir than stem cells collected from adult tissues, ethical considerations have redirected attention upon primitive cells residing in the bone marrow, blood, brain, liver, muscle, and skin, from where they can be harvested with relative sociological impunity. Among these, it is arguably the stem and progenitor cells of the mammalian hematopoietic system that we know most about today, and their intense study in rodents and humans over the past 50 years has culminated in the identification of phenotypic and molecular genetic markers of lineage commitment and the development of functional assays that facilitate their quantitation and prospective isolation. This review focuses exclusively on the biology of hematopoietic stem cells (HSCs) and their immediate progeny. Nevertheless, many of the concepts established from their study can be considered fundamental tenets of an evolving stem cell paradigm applicable to many regenerating cellular systems. PMID:14734085
Szilvassy, Stephen J
Abstract Cardiovascular disease remains a leading cause of mortality in developed nations, despite continued advancement in modern therapy. Progenitor and stem cell–based therapy is a novel treatment for cardiovascular disease, and modest benefits in cardiac recovery have been achieved in small clinical trials. This therapeutic modality remains challenged by limitations of low donor-cell survival rates, transient recovery of cardiac function, and the technical difficulty of applying directed cell therapy. Understanding the signaling mechanisms involved in the stem cell response to ischemia has revealed opportunities to modify directly aspects of these pathways to improve their cardioprotective abilities. This review highlights general considerations of stem cell therapy for cardiac disease, reviews the major proinflammatory signaling pathways of mesenchymal stem cells, and reviews ex vivo modifications of stem cells based on these pathways. Antioxid. Redox Signal. 11, 1883–1896.
Herrmann, Jeremy L.; Markel, Troy A.; Abarbanell, Aaron M.; Weil, Brent R.; Wang, Meijing; Wang, Yue; Tan, Jiangning
Recent breakthroughs in stem cell biology, especially the development of the induced pluripotent stem cell techniques, have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells in regenerative medicine. Stem cell therapies are being considered for the treatment of degenerative diseases, inflammatory conditions, cancer and repair of damaged tissue. The safety of a stem cell therapy depends on many factors including the type of cell therapy, the differentiation status and proliferation capacity of the cells, the route of administration, the intended clinical location, long term survival of the product and/or engraftment, the need for repeated administration, the disease to be treated and the age of the population. Understanding the product profile of the intended therapy is crucial to the development of the nonclinical safety study design.
Sharpe, Michaela E., E-mail: email@example.com [Investigative Toxicology, Drug Safety Research and Development, Pfizer Ltd, Ramsgate Road, Sandwich, CT13 9NJ (United Kingdom); Morton, Daniel [Exploratory Drug Safety, Drug Safety Research and Development, Pfizer Inc, Cambridge, 02140 (United States)] [Exploratory Drug Safety, Drug Safety Research and Development, Pfizer Inc, Cambridge, 02140 (United States); Rossi, Annamaria [Investigative Toxicology, Drug Safety Research and Development, Pfizer Ltd, Ramsgate Road, Sandwich, CT13 9NJ (United Kingdom)] [Investigative Toxicology, Drug Safety Research and Development, Pfizer Ltd, Ramsgate Road, Sandwich, CT13 9NJ (United Kingdom)
As stem cells are a cornerstone of regenerative medicine, research efforts have been extensively focused on controlling their self-renewal and differentiation. It is well known that stem cells are tightly regulated by a combination of physical and chemical factors from their complex extracellular surroundings; thus, conventional cell culture approaches based purely on using soluble factors to direct stem cell fate have resulted in limited success. To account for the complexities of native stem-cell niches, biomaterials are actively investigated as artificial extracellular matrices in order to mimic the natural microenvironment. This Perspective highlights important areas related to the design of biomaterials to control stem cell behavior, such as cell-responsive ligands, mechanical signals, and delivery of soluble factors.
Cha, Chaenyung; Liechty, William B.; Khademhosseini, Ali; Peppas, Nicholas A.
Mesenchymal stem cells have the capacity to differentiate into a variety of connective tissue cells including bone, cartilage, tendon, muscle and adipose tissue. These multipotent cells have been isolated from bone marrow and from other adult tissues including skeletal muscle, fat and synovium. Because of their multipotentiality and capacity for self renewal adult stem cells may represent units of active regeneration of tissues damaged as a result of trauma or disease. In certain degenerative diseases such as osteoarthritis (OA) stem cells are depleted, and have reduced proliferative capacity and reduced ability to differentiate. The delivery of stem cells to these individuals may therefore enhance repair or inhibit the progressive destruction of the joint. We have developed methods for the delivery of mesenchymal stem cell preparations taken from bone marrow to the injured knee joint. This treatment has the potential to stimulate regeneration of cartilage and retard the progressive destruction of the joint that typically occurs following injury. PMID:12708651
Barry, Frank P
Stem cell maintenance is essential for growth and development of plants and animals. Similar to animal studies, transcription factors play a critical role in plant stem cell maintenance, however the regulatory logic is not well understood. Shoot apical meristems (SAMs) harbor a pool of pluoripotent stem cells and they provide cells for the development of all above-ground organs. Molecular genetic studies spanning more than a decade have revealed cell-cell communication logic underlying stem cell homeostasis. WUSCHEL (WUS), a homeodomain transcription factor expressed in cells of the organizing center specifies stem cells in overlying cells of the central zone (CZ) and also activates a negative regulator-CLAVATA3 (CLV3). CLV3, a small secreted peptide, binds to CLAVATA1 (CLV1) and also possibly to CLV1-related receptors to activate signaling which restricts WUS transcription. Though the CLV-WUS feedback network explains the cell-cell communication logic of stem cell maintenance, how WUS communicates with adjacent cells had remained elusive. In October 15 2011 issue of Genes and Development, we report that WUS protein synthesized in cells of organizing center migrates into adjacent cells via cell-cell movement and activates CLV3 transcription by directly binding to promoter elements.
Yadav, Ram Kishor; Reddy, G. Venugopala
Due to their unique capacity for self-renewal in addition to their ability to differentiate into cells of all neuronal lineages, neuronal stem cells (NSCs) are promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. However, there are few studies on immune rejection, which is one of the main problems facing successful stem cell therapy. In order to
Eun Mi Lee; Jae Young Kim; Bum Rae Cho; Woo Kyung Chung; Byung-Woo Yoon; Seung U. Kim; Byeong Chun Lee; Woo Suk Hwang; Shin-Yong Moon; Jung Sang Lee; Curie Ahn
Researchers may be interested to know that the journal Stem Cells is offering full content for free during a trial period that has been extended until further notice (for at least three months). The forthcoming issue leads off with an editorial devoted to the new registry, "National Stem Cell Resource: Stem Cells Find a Niche," by Robert G. Hawley.
Vision loss is a major social issue, with more than 20 million people over the age of 18 years affected in the USA alone. Loss of vision is feared more than premature death or cardiovascular disease, according to a recent Society for Consumer Research group survey. The annual direct cost of medical care for the most prevalent eye disease, age-related macular degeneration, was estimated at US$255 billion in 2010 with an additional economic impact of US$88 billion due to lost productivity and the burden of family and community care for visual disability. With the blossoming of human stem cell research, regenerative treatments are now being developed that can help reduce this burden. Positive results from animal studies demonstrate that stem cell-based transplants can preserve and potentially improve vision. This has led to new clinical trials for several eye diseases that are yielding encouraging results. In the next few years, additional trials and longer-term results are anticipated to further develop ocular regenerative therapies, with the potential to revolutionize our approach to ophthalmic disease and damage. PMID:23210809
Blenkinsop, Timothy A; Corneo, Barbara; Temple, Sally; Stern, Jeffrey H
Vision loss is a major social issue, with more than 20 million people over the age of 18 years affected in the USA alone. Loss of vision is feared more than premature death or cardiovascular disease, according to a recent Society for Consumer Research group survey. The annual direct cost of medical care for the most prevalent eye disease, age-related macular degeneration, was estimated at US$255 billion in 2010 with an additional economic impact of US$88 billion due to lost productivity and the burden of family and community care for visual disability. With the blossoming of human stem cell research, regenerative treatments are now being developed that can help reduce this burden. Positive results from animal studies demonstrate that stem cell-based transplants can preserve and potentially improve vision. This has led to new clinical trials for several eye diseases that are yielding encouraging results. In the next few years, additional trials and longer-term results are anticipated to further develop ocular regenerative therapies, with the potential to revolutionize our approach to ophthalmic disease and damage.
Blenkinsop, Timothy A; Corneo, Barbara; Temple, Sally; Stern, Jeffrey H
The cancer stem cell (CSC) model provides insights into pathophysiology of cancers and their therapeutic response. The CSC model has been both controversial, yet provides a foundation to explore cancer biology. In this review, we provide an overview of CSC concepts, biology and potential therapeutic avenues. We then focus on prostate CSC including (1) their purported origin as either basal-derived or luminal-derived cells; (2) markers used for prostate CSC identification; (3) alterations of signaling pathways in prostate CSCs (4) involvement of prostate CSCs in metastasis of PCa and (5) microRNA-mediated regulation of prostate CSCs. Although definitive evidence for the identification and characterization of prostate CSCs still remains unclear, future directions pursuing therapeutic targets of CSCs may provide novel insights for the treatment of PCa.
Yu, Chunyan; Yao, Zhi; Jiang, Yuan; Keller, Evan. T.
Stem cells are capable of renewing themselves through cell division and have the remarkable ability to differentiate into many different types of cells. They therefore have the potential to become a central tool in regenerative medicine. During the last decade, advances in tissue engineering and stem cell-based tooth regeneration have provided realistic and attractive means of replacing lost or damaged teeth. Investigation of embryonic and adult (tissue) stem cells as potential cell sources for tooth regeneration has led to many promising results. However, technical and ethical issues have hindered the availability of these cells for clinical application. The recent discovery of induced pluripotent stem (iPS) cells has provided the possibility to revolutionize the field of regenerative medicine (dentistry) by offering the option of autologous transplantation. In this article, we review the current progress in the field of stem cell-based tooth regeneration and discuss the possibility of using iPS cells for this purpose.
Otsu, Keishi; Kumakami-Sakano, Mika; Fujiwara, Naoki; Kikuchi, Kazuko; Keller, Laetitia; Lesot, Herve; Harada, Hidemitsu
Summary Aim Stem cell research in recent years have been considered the most advanced sort of medical-scientific research and early results have aroused great expectations. Also in dentistry many studies were performed with the final aim of obtaining new bone and new teeth. In this work we describe the state of the art in dental science stem cell research. Methods We have performed a web-based research on MEDLINE within (www.pubmed.gov). We have used “stem cells from human exfoliated deciduous teeth” (24 paper found), “periodontal ligament stem cells” (32 paper found), “stem cell apical papilla” (16 paper found), “dental pulp stem cells” (136 paper found) as keywords for research. For each keyword we have performed a complete review focusing on knowledge upgrade. Results For each topic was created a selection of papers in chronological order of publication date so to give a timetable of the development of the research for each niche. Conclusion Research about stem cell from oral niches began in 2000 and every year papers publicated were more than the precedent. This review analysed about 180 articles most of which in the last 5 years. Dentla pulp from adult as from deciduous teeth seems to be the most valuable font of stem cells due to the pluripotential type of cells.
Giordano, Guido; La Monaca, Gerardo; Annibali, Susanna; Cicconetti, Andrea; Ottolenghi, Livia
This review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up-regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity. PMID:24484934
Insinga, Alessandra; Cicalese, Angelo; Pelicci, Pier Giuseppe
Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell–based therapy of age-related diseases.
The administration of exogenous stem cells offers promise to regenerate many damaged organs. However, failures of these cellular therapies could be related to many issues, such as the type of stem cell, the dose of cellular therapeutic, dosing regime, and mode of delivery. The recent ability to directly label stem cells with magnetic resonance (MR) contrast agents provides a simple, straight-forward manner to monitor accurate cell delivery and track stem cells non-invasively in a serial manner. Provided here is an overview of the currently available MR-labeling methods, including direct non-specific labeling with contrast agents, indirect specific labeling with contrast agents, labeling with MRI reporter genes, and fluorine hot spot labeling. Several of these approaches have now been applied successfully in preclinical animal models of cardiovascular disease. Once properly implemented, future clinical trials may benefit greatly from imaging stem cells with MRI.
Bulte, Jeff W. M.
The fundamental basis of our work is that organs are generated by multipotent stem cells, whose properties we must understand to control tissue assembly or repair. Central nervous system (CNS) stem cells are now recognized as a well-defined population of precursors that differentiate into cells that are indisputably neurons and glial cells. Work from our group played an important role in defining stem cells of the CNS. Embryonic stem (ES) cells also differentiate to specific neuron and glial types through defined intermediates that are similar to the cellular precursors that normally occur in brain development. There is convincing evidence that the differentiated progeny of ES cells and CNS stem cells show expected functions of neurons and glia. Recent progress has been made on three fundamental developmental processes: (i) cell cycle control; (ii) the control of cell fate; and (iii) early steps in neural differentiation. In addition, our work on CNS stem cells has developed to a stage where there are clinical implications for Parkinson's and other degenerative disorders. These advances establish that stem cell biology contributes to our understanding of brain development and has great clinical promise.
McKay, R D