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PubMed2006

Bone reconstruction with bone marrow stromal cells.

Bone marrow stromal/stem cells (BMSCs) are multipotent adult stem cells and have become the important cell source for cell therapy and engineered tissue repair. Their osteogenic differentiation potential has been well characterized in many in vitro studies. In addition, small animal model-based studies also reveal their capability of bone formation in vivo when implanted with biodegradable scaffold, indicating the great potential for therapeutic application. Bone defect is a common clinical problem that deserves an optimal therapy. Unlike traditional surgical repair that needs to sacrifice donor site tissue, the tissue-engineering approach can achieve the goal of bone regeneration and repair without the necessity of donor site morbidity. To safely translate experimental study into a clinical trial of engineered bone repair, in vivo study using large animal models has become the key issue. Our in vivo study in this aspect and the published results indicate that bone regeneration and repair by BMSCs and biodegradable scaffold is a realistic goal that can be achieved.

Animals↗
PubMed2004

Cerebellar granule cell precursors can differentiate into astroglial cells.

During CNS development, multipotent neural stem cells give rise first to various kinds of specified precursor cells, which proliferate extensively before terminally differentiating into either neurons or glial cells. It is still not clear, however, whether the specified precursor cells are irreversibly determined to differentiate into their particular cell types. In this study, we show that isolated mouse cerebellar granule cell precursors from the outermost, proliferative zone of the external germinal layer can differentiate into astroglial cells when exposed to sonic hedgehog (Shh) and bone morphogenetic proteins. These induced cells initially expressed both glial fibrillary acidic protein and neuronal markers, but they then lost their neuronal markers and acquired S100-beta, a marker of differentiated astroglial cells. These results indicate that at least some granule cell precursors are not irreversibly committed to neuronal development but can be induced to differentiate into astroglial cells by appropriate extracellular signals.

Animals↗
PubMed2005

Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells.

Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2alpha mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2alpha leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2alpha plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

Animals↗
PubMed2005

Expression of cardiomyocytic markers on adipose tissue-derived cells in a murine model of acute myocardial injury.

Animal and early clinical studies have provided evidence suggesting that intracoronary administration of autologous bone marrow-derived cells results in improved outcome following myocardial infarction. Animal studies with cultured marrow stromal cells (MSC) have provided similar data. Cells with properties that are similar to MSC have been identified in adipose tissue. Other groups have demonstrated in vivo differentiation of adipose tissue-derived cells (ADC) into cells exhibiting biochemical and functional markers of cardiac myocytes, including spontaneous beating. Based on these observations, the objective of the present study was to determine whether ADC might undergo similar differentiation in vivo in the context of myocardial injury.ADC were isolated from subcutaneous adipose tissue of Rosa26 mice (which express the beta-galactosidase transgene in almost every tissue) and injected into the intraventricular chamber of B6129S recipient mice immediately following induction of myocardial cryoinjury. Groups of recipients were euthanized at 24 hours, 7 and 14 days post surgery and examined for the presence of donor-derived cells within the heart.Beta-gal positive cells were identified in the infarcts of ADC-treated animals. No staining was observed in uninjured myocardium or in infarcts of control animals. Immunohistochemical analysis revealed co-expression of beta-gal with Myosin Heavy Chain, Nkx2.5 and with Troponin I. Co-expression of beta-galactosidase with Connexin 43, CD31, von Willebrand factor, MyoD or CD45 was not detected.Thus, these data indicate that adipose tissue contains a population of cells that has the ability to engraft injured myocardium and that this engraftment is associated with expression of cardiomyocytic markers by donor-derived cells.

Adipocytes↗
PubMed2004

Stem sense: a proposal for the classification of stem cells.

Stem cells, while difficult to define, hold great promise as tools for understanding development and as therapy. However, this difficulty in defining stem cells has led to a multiplicity of stem cells that may or may not be distinct. The lack of common standards or definitions, the absence of a common forum for discussion, and the range in the ability to manipulate his/her favorite system of stem cells has led to further fragmentation of a field bedeviled by controversy. I suggest that stratification and classification of stem cells on the basis of their function, characteristics, and capabilities would be of enormous benefit to the community. This absence of uniform nomenclature and classification has led to many contradictory claims as to the abilities of stem cells and has made it very difficult to generalize across systems and cell types. I illustrate the problem by providing two examples of how the lack of uniform definitions has slowed progress. I suggest that the effort to establish a consensus on what constitutes a tissue-specific stem cell (definition) and how one would stratify cells (classification) would greatly facilitate progress and perhaps help resolve some of the outstanding controversies.

Animals↗
PubMed2004

Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow.

Transdifferentiation is a process whereby one cell type committed to and progressing along a specific developmental lineage switches into another cell type of a different lineage through genetic reprogramming. Even though this process has been well studied and established in amphibian systems, it is unclear if mammalian cells possess the same potential. Recent in vivo transplantation studies showed that adult mesenchymal stem cells (MSCs) were able to differentiate into mesoderm-derived cell types as well as cells with neuroectodermal and endodermal characteristics, suggesting that transdifferentiation occurs in mammalian systems. However, there are concerns over these findings because of the possibility of progenitor cell contamination and cell fusion. In this study, we have developed an in vitro differentiation strategy to assess if human MSCs that have differentiated into a given mesenchyme cell lineage can transdifferentiate into other cell types in response to inductive extracellular cues. Our results showed that fully differentiated cells from hMSCs were capable of dedifferentiation and transdifferentiation into cells of another developmental lineage at single cell levels.

Adipocytes↗
PubMed2006

Guidance of neural crest cell migration: the inhibitory function of the chondroitin sulfate proteoglycan, versican.

Neural crest cells are specialized multipotent embryonic stem cells found exclusively in vertebrates[1,2,3]. During embryonic development, these cells arise from the dorsal neural tube, undergo epithelial to mesenchymal transition, and subsequently migrate along stereotyped pathways to reach specific tissue targets, where they differentiate into a wide variety of cell types, such as glia and neurons of the peripheral nervous system, melanocytes, smooth muscle cells, craniofacial cartilage and bone tissues, or chromaffin cells of the adrenal medulla. In the trunk region, the ventrally migrating neural crest cells move through the somitic mesenchyme in a segmented pattern, presumably setting the basis for the metameric organization of sensory and sympathetic ganglia along the anterior-posterior axis later in development[4].

Animals↗
PubMed2005

Anomalous megakaryocytopoiesis in mice with mutations in the c-Myb gene.

Mpl(-/-) mice bearing the Plt3 or Plt4 mutations in the c-Myb gene exhibit thrombopoietin (TPO)-independent supraphysiological platelet production accompanied by excessive megakaryocytopoiesis and defective erythroid and lymphoid cell production. To better define the cellular basis for the thrombocytosis in these mice, we analyzed the production and characteristics of megakaryocytes and their progenitors. Consistent with thrombocytosis arising from hyperactive production, the high platelet counts in mice carrying the c-Myb(Plt4) allele were not accompanied by any significant alteration in platelet half-life. Megakaryocytes in c-Myb mutant mice displayed reduced modal DNA ploidy and, among the excessive numbers of megakaryocyte progenitor cells, more mature precursors were particularly evident. Megakaryocyte progenitor cells carrying the Plt3 or Plt4 c-Myb mutations, but not granulocyte-macrophage progenitors, exhibited 200-fold enhanced responsiveness to granulocyte-macrophage colony-stimulating factor (GM-CSF), suggesting that altered responses to cytokines may contribute to expanded megakaryocytopoiesis. Mutant preprogenitor (blast colony-forming) cells appeared to have little capacity to form megakaryocyte progenitor cells. In contrast, the spleens of irradiated mice 12 days after transplantation with mutant bone marrow contained abundant megakaryocyte progenitor cells, suggesting that altered c-Myb activity skews differentiation commitment in spleen colony-forming units (CFU-S) in favor of excess megakaryocytopoiesis.

Alleles↗
PubMed2006

Satellite cells isolated from adult Hanwoo muscle can proliferate and differentiate into myoblasts and adipose-like cells.

This study examined whether adult bovine muscle satellite cells from 30-month-old Hanwoo cattle are multipotential. The satellite cells were found to have the potential to proliferate and differentiate into myoblasts with the formation of multinucleated cells. In addition, treatment with the peroxisome proliferator activating receptor-gamma (PPARgamma) agonist, rosiglitazone, promoted their trans-differentiation into adipocytes with significant increases in glycerol accumulation and glycerol-3-phosphate dehydrogenase activity. Western blot analysis revealed that increased levels of the adipocyte fatty acid-binding protein, PPARgamma and of CCAAT/enhancer-binding protein were closely related to rosiglitazone-induced differentiation of the cells. These findings demonstrate that satellite cells from adult Hanwoo cattle are multipotent, and that their trans-differentiation into adipocytes can be induced by rosiglitazone.

Adipocytes↗
PubMed2002

Transplantation of an indigenous neural stem cell population leading to hyperplasia and atypical integration.

Astrocytes exhibit neural stem cell characteristics in vitro by generating multipotent clones of cells. In order to see if normal cues are present in vivo that can direct these astrocytes to generate cells of neuronal lineage, the astrocytes were transplanted into the persistently neurogenic mouse subependymal zone/rostral migratory stream. Grafted astrocytes assumed migratory profiles, joined chains of indigenous neuroblasts, and migrated into the olfactory bulb. Additionally, however, some grafted astrocytes "homed" to the lateral ventricle where they became hyperplastic, forming spherical structures composed of cells of mixed phenotype that attached to the ventricular wall, and eventually penetrated and dispersed within surrounding brain parenchyma. It is proposed that, with an interest in the use of stem cell transplants for neurological disease, findings of hyperplasia and apparent atypical integration of a native population of multipotent astrocytic stem cells suggest the need for caution before beginning even autologous neural stem cell transplants.

Animals↗
PubMed2004

Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL(+) multipotent adult progenitor cell clones from peripheral blood.

BACKGROUND: The CD34(-) murine stem cell line RM26 cloned from peripheral blood mononuclear cells has been shown to generate hematopoietic progeny in lethally irradiated animals. The peripheral blood-derived cell clones expresses a variety of mesodermal and erythroid/myeloid transcription factors suggesting a multipotent differentiation potential like the bone marrow-derived 'multipotent adult progenitor cells' (MAP-C). METHODS: SCL(+) CD34(-) RM26 cells were transfused intravenously into mice suffering from chronic hind-limb ischemia, evaluating the effect of stem cells on collateral artery growth and simultaneous skeletal muscle repair. RESULTS: RM26 cells are capable of differentiating in vitro into endothelial cells when cultured on the appropriate collagen matrix. Activation of the SCL stem cell enhancer (SCL(+)) is mediated through the binding to two Ets and one GATA site and cells start to express milieu- and growth condition-dependent levels of the endothelial markers CD31 (PECAM) and Flt-1 (VEGF-R1). Intravenously infused RM26 cells significantly improved the collateral blood flow (arteriogenesis) and neo-angiogenesis formation in a murine hind-limb ischemia transplant model. Although transplanted RM26 cells did not integrate into the growing collateral arteries, cells were found adjacent to local arteriogenesis, but instead integrated into the ischemic skeletal muscle exclusively in the affected limb for simultaneous tissue repair. CONCLUSION: These data suggest that molecularly primed hem-/mesangioblast-type adult progenitor cells can circulate in the peripheral blood improving perfusion of tissues with chronic ischemia and extending beyond the vascular compartment.

Animals↗
PubMed2002

Alternative views of tissue stem cell plasticity.

Stem cells have traditionally been characterized as either embryonic (pluripotent) or tissue-specific (multipotent). Thus, tissue-specific stem cells generate the cell types comprising a particular tissue in embryos and, in some cases, adults. A recent series of studies, however, has challenged the notion of lineage restriction in multipotent stem cells. These experiments have been interpreted as evidence that stem cells from one tissue can be induced to differentiate into cells of other organs, either in vitro or after transplantation in vivo. This paper reviews the current evidence for stem cell plasticity. Some of the potential caveats to the current work are also discussed and, finally, the potential underlying mechanisms of stem cell plasticity are examined.

Animals↗
PubMed2004

Regulatory elements of the vav gene drive transgene expression in hematopoietic stem cells from adult mice.

OBJECTIVE: Previous studies have shown that the HS21/45 promoter of the vav protooncogene drives a predominant expression of exogenous transgenes in mouse hematopoietic cells, including clonogenic bone marrow (BM) progenitors. We investigated the activity of this promoter in the hematopoietic stem cell compartment of adult mice. MATERIALS AND METHODS: Inbred Ly5.1 transgenic mice expressing a nonfunctional human CD4 marker gene (hCD4) under the control of the HS21/45 promoter were generated. BM cells from these animals were sorted based on the intensity of hCD4 expression. Fractions characterized by high, intermediate, or low/negative expression of the transgene were then assessed for their competitive repopulation ability (CRA), using unfractionated BM cells from Ly5.2 mice as a reference competitor population. RESULTS: Data showed that BM cells having a low/negative or intermediate expression of hCD4 had a very poor hematopoietic CRA. In contrast, BM cells with high hCD4 expression were characterized by a high CRA. These observations were confirmed in the short- and long-term posttransplantation of primary and secondary recipients when analyzing the lymphoid and myeloid cells of recipient mice. CONCLUSIONS: Our results demonstrate for the first time that the regulatory HS21/45 sequence of the vav gene constitutes an efficient promoter for driving transgene expression in multipotent hematopoietic stem cells residing in the BM of adult mice. Thus, this promoter is proposed for the development of transgenic mice and gene therapy vectors that require restricted expression of exogenous transgenes in cells of the hematopoietic system, including primitive hematopoietic stem cells.

Animals↗
PubMed2005

Cardiac stem cells and myocardial regeneration.

Until recently, the accepted paradigm considered the adult mammalian heart a post-mitotic organ without intrinsic regenerative capacity where neither myocyte death nor new myocyte formation played any role in its homeostasis and could be safely ignored. We have recently identified in the adult mammalian myocardium a small cell population expressing surface antigens commonly associated with a variety of stem cells. These cells have the behaviour and potential of bonafide cardiac stem cells (CSCs): they are clonogenic, self-renewing and multipotent. Their presence has identified myocyte death and myocyte renewal as the two sides of the proverbial coin of cardiac homeostasis. Myocyte renewal depends on the differentiation of the CSCs into immature myocytes that divide two to four times before becoming terminally differentiated. Both in vivo and in vitro the progeny of a single CSC can generate the three major cell types of the myocardium: myocytes, smooth muscle and endothelial vascular cells. More interestingly, when directly injected or activated with growth factors in the post-ischaemic myocardium, these cells are able to reconstitute a functional ventricular wall. Thus, although in the adult heart most cardiac myocytes are permanently withdrawn from the cell cycle, the heart has an intrinsic regenerative potential and it is not a terminally differentiated organ.

Animals↗
PubMed1996

Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro.

To understand the mechanism of the sequential restriction of multipotency of stem cells during development, we have established culture conditions that allow the differentiation of neuroepithelial precursor cells from embryonic stem (ES) cells. A highly enriched population of neuroepithelial precursor cells derived from ES cells proliferates in the presence of basic fibroblast growth factor (bFGF). These cells differentiate into both neurons and glia following withdrawal of bFGF. By further differentiating the cells in serum-containing medium, the neurons express a wide variety of neuron-specific genes and generate both excitatory and inhibitory synaptic connections. The expression pattern of position-specific neural markers suggests the presence of a variety of central nervous system (CNS) neuronal cell types. These findings indicate that neuronal precursor cells can be isolated from ES cells and that these cells can efficiently differentiate into functional post-mitotic neurons of diverse CNS structures.

Animals↗