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Results for “Multipotent Stem Cells”

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PubMed2005

Characterization of multipotent mesenchymal stem cells from the bone marrow of rhesus macaques.

The isolation and characterization of embryonic and adult stem cells from higher-order mammalian species will enhance the understanding of the biology and therapeutic application of stem cells. The aim of this study was to purify rhesus mesenchymal stem cells (MSCs) from adult bone marrow and to characterize functionally their abilities to differentiate along diverse lineages. Adherent cells from adult rhesus macaque bone marrow were characterized for their growth characteristics, lineage differentiation, cell-surface antigen expression, telomere length, chromosome content, and transcription factor gene expression. Rhesus bone marrow MSCs (BMSCs) are very heterogeneous, composed of primarily long, thin cells and some smaller, round cells. The cells are capable of differentiating along osteogenic, chondrogenic, and adipogenic lineages in vitro. The cell morphology and multipotential differentiation capabilities are maintained throughout extended culture. They express CD59, CD90 (Thy-1), CD105, and HLA-1 and were negative for hematopoietic markers such as CD3, CD4, CD8, CD11b, CD13, CD34, and platelet endothelial cell adhesion molecule-1 (CD31). BMSCs were also demonstrated to express the mRNA for important stem cell-related transcription factors such as Oct-4, Sox-2, Rex-1, and Nanog. Rhesus BMSCs have a normal chromosome content, and the shortening of telomeres is minimal during early passages. These data demonstrate that BMSCs isolated from rhesus macaques have a high degree of commonality with MSCs isolated from other species. Therefore, isolation of these cells provides an effective and convenient method for rapid expansion of pluripotent rhesus MSCs.

Adipocytes↗

PubMed2002

Stem cells--clinical application and perspectives.

BACKGROUND: Augmentation of myocardial performance in experimental models of therapeutic infarction and heart failure has been achieved by transplantation of exogenous cells into damaged myocardium. The quest for suitable donor cells has prompted research into the use of both embryonic stem cells and adult somatic stem cells. MULTIPOTENT SOMATIC STEM CELLS: Recently, there has been a growing body of evidence that multipotent somatic stem cells in adult bone marrow exhibit tremendous functional plasticity and can reprogram in a new environmental tissue niche to give rise to cell lineages specific for new organ site. This phenomenon has made huge impact on myocardial biology, while multipotent adult bone marrow hematopoeitic stem cells and mesechymal stem cells can repopulate infarcted rodent myocardium and differentiate into both cardiomyocytes and new blood vessels. CONCLUSION: These data, coupled with the identification of a putative primitive cardiac stem cell population in the adult human heart, may open the way for novel therapeutic modalities for enhancing myocardial performance and treating heart failure.

Adult↗

PubMed2002

Cell-intrinsic and cell-extrinsic cues regulating lineage decisions in multipotent neural crest-derived progenitor cells.

Multipotent stem cells must generate various differentiated cell types in correct number and sequence during neural development. In the peripheral nervous system (PNS), this involves the formation of postmigratory progenitor cell types which maintain multipotency and are able to give rise to neural and non-neural cells in response to instructive growth factors. We propose that fate restrictions in such progenitor cells are controlled by the combinatorial interaction of different extracellular signals, including community effects in response to both neurogenic and gliogenic factors. In addition, distinct progenitor cell types display intrinsic differences which modulate their response to the extracellular environment. Thus, a progenitor cell is apparently able to integrate multiple intrinsic and extrinsic cues and thereby to choose fates appropriate for its location. Fate analysis of genetically modified progenitor cells will help to identify the molecules involved. This approach appears promising given the identification of multipotent progenitor cells from the mouse PNS and the availability of genetics in the mouse system.

Animals↗

PubMed2002

Contractile responses of smooth muscle cells differentiated from rat neural stem cells.

To characterize the functional differentiation of neural stem cells into smooth muscle cells, multipotent stem cells in the central nervous system (CNS) were isolated from rat embryonic day 14 (E14) cortex and cultured by neurosphere formation in serum-free medium in the presence of 10 ng ml(-1) of basic fibroblast growth factor. Differentiation was induced by the addition of 10 % fetal bovine serum to low-density cultures (2.5 x 10(3) cells cm(-2)). Immunological analyses and reverse transcriptase-polymerase chain reaction indicated that the differentiated cells expressed smooth-muscle-specific marker proteins such as SM-1, SM-2, and SMemb myosin heavy chains, SM-22, basic calponin and alpha-smooth-muscle actin, but not the astrocyte marker glial fibrillary acidic protein. To examine whether smooth-muscle-like cells that are differentiated from CNS stem cells possess the characteristics of contractile smooth muscle, we prepared reconstituted collagen gel fibres and measured their contractile tension. The reconstituted fibres were prepared by thermal gelation of collagen and the differentiated cells. The fibres contracted in response to treatment with KCl (80 mM), ACh (100 microM), endothelin-1 (10 nM), endothelin-2 (10 nM), and prostaglandin F2alpha (100 microM). ACh-induced contraction was partially inhibited by the L-type voltage-dependent Ca(2+) channel inhibitor nifedipine and by the intracellular Ca(2+) chelator 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, the myosin light chain kinase inhibitor ML-9, the Rho kinase inhibitor Y-27632, dibutyryl cAMP and 8-bromo-cGMP. These results suggest that CNS stem cells give rise to smooth muscle cells in vitro that have an identical contractile function to smooth muscle in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain.

The subventricular zone (SVZ) of the adult mammalian forebrain contains kinetically distinct precursor populations that contribute new neurons to the olfactory bulb. Because among forebrain precursors there are stem-like cells that can be cultured in the presence of mitogens such as epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), we asked whether distinct subsets of stem-like cells coexist within the SVZ or whether the proliferation of a single type of SVZ stem-like cell is controlled by several GFs. We show that the latter is the case. Thus cells isolated from the SVZ coexpress the EGF and FGF receptors; by quantitative analysis, the number of stem-like cells isolated from the SVZ by either FGF2 or EGF is the same, whereas no additive effect occurs when these factors are used together. Furthermore, short-term administration of high-dose [3H]thymidine in vivo depletes both the EGF- and FGF2-responsive stem-like cell populations equally, showing they possess closely similar proliferation kinetics and likely belong to the constitutively proliferating SVZ compartment. By subcloning and population analysis, we demonstrate that responsiveness to more than one GF endows SVZ cells with an essential stem cell feature, the ability to vary self-renewal, that was until now undocumented in CNS stem-like cells. The multipotent stem cell-like population that expands slowly in the presence of FGF2 in culture switches to a faster growth mode when exposed to EGF alone and expands even faster when exposed to both GFs together. Analogous responses are observed when the GFs are used in the reverse order, and furthermore, these growth rate modifications are fully reversible.

Animals↗

PubMed1997

Glial-restricted precursors are derived from multipotent neuroepithelial stem cells.

Neuroepithelial cells in the developing ventricular zone differentiate into neurons, astrocytes, and oligodendrocytes. It is not known, however, whether this differentiation occurs in a single step or is a pathway utilizing intermediate more restricted precursor cells. To characterize the generation of glial cells from multipotent stem cells we have cultured neuroepithelial (NEP) cells from E10.5 rat embryos. Cultured NEP cells do not express any glial differentiation markers when grown on fibronectin/laminin under nondifferentiation conditions. NEP cells, however, differentiate into A2B5 immunoreactive cells which can subsequently give rise to oligodendrocytes and astrocytes. Clonal analysis of NEP cells demonstrates that the A2B5 immunoreactive cells arise in clones that contain neurons and astrocytes, indicating that A2B5(+) cells arise from multipotent NEP precursor cells. A2B5(+) cells, maintained as undifferentiated cells over multiple passages, can subsequently give rise to both oligodendrocytes and astrocytes. A2B5(+) cells, however, do not generate neurons. Thus A2B5(+) cells represent a restricted progenitor cell population that differentiates from a multipotent NEP cell. Based on our results we propose that differentiation of the multipotential NEP cells to terminally differentiated glial cells occurs via intermediate restricted precursors.

Animals↗

PubMed2001

Immature neurons from CNS stem cells proliferate in response to platelet-derived growth factor.

Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.

Animals↗

PubMed2004

Existence of reserve quiescent stem cells in adults, from amphibians to humans.

Several theories have been proposed to explain the phenomenon of tissue restoration in amphibians and higher order animals. These theories include dedifferentiation of damaged tissues, transdifferentiation of lineage-committed stem cells, and activation of quiescent stem cells. Young and colleagues demonstrated that connective tissues throughout the body contain multiple populations of quiescent lineage-committed progenitor stem cells and lineage-uncommitted pluripotent stem cells. Subsequent cloning and cell sorting studies identified quiescent lineage-uncommitted pluripotent mesenchymal stem cells, capable of forming any mesodermal cell type, and pluripotent epiblastic-like stem cells, capable of forming any somatic cell type. Based on their studies, they propose at least 11 categories of quiescent reserve stem cells resident within postnatal animals, including humans. These categories are pluripotent epiblastic-like stem cells, pluripotent ectodermal stem cells, pluripotent epidermal stem cells, pluripotent neuronal stem cells, pluripotent neural crest stem cells, pluripotent mesenchymal (mesodermal) stem cells, pluripotent endodermal stem cells, multipotent progenitor stem cells, tripotent progenitor stem cells, bipotent progenitor stem cells, and unipotent progenitor stem cells. Thus, activation of quiescent reserve stem cells, i.e., lineage-committed progenitor stem cells and lineage-uncommitted pluripotent stem cells, resident within the connective tissues could provide for the continual maintenance and repair of the postnatal organism after birth.

Adult↗

PubMed2005

Haematopoietic stem cells and repair of the ischaemic heart.

HSCs (haematopoietic stem cells) are multipotent stem cells that give rise to all cells of the blood cell lineage. In recent years, it has been proposed that bone marrow serves as a reservoir for cardiomyogenic precursors and that, following cardiac injury, these stem cells circulate to the site of injury where they contribute to myocardial repair and regeneration. This concept of stem cell plasticity has been controversial and, in fact, several key studies on the cardiomyogenic potential of HSCs have not been reproducible in the hands of independent investigators. Despite this controversy, the clinical community has pushed forward with clinical trials of bone marrow transplantation for the treatment of ischaemic heart disease. The following review summarizes the mechanistic underpinnings of bone marrow transplantation into ischaemic myocardium, focusing on the basic science that forms the foundation of this field, and highlights the controversies and new avenues for research that have emerged. It also describes the current state of the art in clinical trials of bone marrow transplantation for heart failure.

Animals↗

PubMed2005

Stem cell therapy for osteonecrosis of the femoral head.

Aseptic non-traumatic osteonecrosis of the femoral head is a painful disorder of the hip that can lead to femoral head collapse and the need for total hip replacement. As osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into the necrotic lesion could be of benefit in this condition. Indeed, bone marrow contains adult stem cells, such as haematopoietic stem cells, mesenchymal stem cells and multipotent stem cells, that might have osteogenic properties. The efficacy of bone marrow implantation into the osteonecrotic zone was studied in two prospective trials. This treatment avoided the progression of the disease to the stage of the subchondral fracture (stage III) and reduced the need for total hip replacement. The mechanisms involved might include improved osteogenesis and angiogenesis. This new therapeutic approach should modify the treatment of early-stage osteonecrosis of the femoral head.

Femur Head Necrosis↗

PubMed2000

Cell contact regulates fate choice by cortical stem cells.

Cell fate is determined by intrinsic programs and external cues, such as soluble signals and cell-cell contact. Previous studies have demonstrated the roles of soluble factors in the proliferation and differentiation of cortical stem cells and cell-cell contact in maintaining stem cells in a proliferative state. In the present study, we focused on the effect of cell-cell interaction on cell-fate determination. We found that density could exert a strong influence on the cell-type composition when cortical stem cells differentiate. Multipotent stem cells, which normally gave rise to neurons, astrocytes, and oligodendrocytes under high-density culture condition, differentiated almost exclusively into smooth muscle at low density. Clonal analysis indicated that smooth muscle and astrocytes were derived from a common precursor and that the density effect on cell types used an instructive mechanism on the choice of fate rather than an effect of selective survival and/or proliferation. This instructive mechanism depended on the local and not the average density of the cells. This local signal could be mimicked by membrane extract. These findings demonstrate the importance of membrane-bound signals in specifying lineage and provide the first evidence for a short-range regulatory mechanism in cortical stem cell differentiation.

Animals↗

PubMed2006

A comparison study in the proteomic signatures of multipotent germline stem cells, embryonic stem cells, and germline stem cells.

Germline stem (GS) cells can only differentiate into germline cells, while multipotent germ stem (mGS) cells, like embryonic stem (ES) cells, can differentiate into various somatic cells and tissues. The proteomic profiles in GS and mGS cells were compared by two-dimensional gel electrophoresis. Ten down-regulated and 16 up-regulated proteins were differentially expressed in mGS cells in comparison to GS cells, and these proteomic characteristics were very much similar to those in ES cells indicating that multipotency of mGS and ES cells is based on a common molecular event(s). Protein identification by mass spectrometry revealed that these proteins were functionally involved in cell signaling, transcription factors, metabolism, and protein folding. The identified proteins in the present study may thus reveal its biological characteristics and functional property in self-renewal and multipotency.

Animals↗

PubMed2003

Adult cardiac stem cells are multipotent and support myocardial regeneration.

The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.

Animals↗

PubMed2004

Muscle-derived stem cells.

Researchers have identified 2 types of stem cells in skeletal muscle: satellite cells and multipotent stem cells (MPSCs). The latter category includes different cell populations isolated by various researchers using several techniques. The methods used to isolate these cells appear to influence the stem cell characteristics of the MPSCs. Although MPSCs and satellite cells could represent different stages of maturation of the same progenitor cells, they also could represent distinct populations of stem cells that exist in skeletal muscle. This article summarizes the recent developments in muscle-derived stem cell research.

Animals↗

PubMed2006

Phenotypic and functional heterogeneity of GFAP-expressing cells in vitro: differential expression of LeX/CD15 by GFAP-expressing multipotent neural stem cells and non-neurogenic astrocytes.

Recent findings show that the predominant multipotent neural stem cells (NSCs) isolated from postnatal and adult mouse brain express glial fibrillary acid protein (GFAP), a protein commonly associated with astrocytes, and that primary astrocyte cultures can contain GFAP-expressing cells that act as multipotent NSCs when transferred to neurogenic conditions. The relationship of GFAP-expressing NSCs to GFAP-expressing astrocytes is unclear, but has important implications. We compared the phenotype and neurogenic potential of GFAP-expressing cells derived from different CNS regions and maintained in vitro under different conditions. Multiple labeling immunohistochemistry revealed that both primary astrocyte cultures and adherent neurogenic cultures derived from postnatal or adult periventricular tissue contained subpopulations of GFAP-expressing cells that co-expressed nestin and LeX/CD15, two molecules associated with NSCs. In contrast, GFAP-expressing cells in similar cultures prepared from adult cerebral cortex did not express detectable levels of LeX/CD15, and exhibited no neurogenic potential. Fluorescence-activated cell sorting (FACS) of both primary astrocyte cultures and adherent neurogenic cultures for LeX/CD15 showed that GFAP-expressing cells competent to act as multipotent NSCs were concentrated in the LeX-positive fraction. Using neurosphere assays and a transgenic ablation strategy, we confirmed that the predominant NSCs in primary astrocyte and adherent neurogenic cultures were GFAP-expressing cells. These findings demonstrate that GFAP-expressing cells derived from postnatal and adult forebrain are heterogeneous in both molecular phenotype and neurogenic potential in vitro, and that this heterogeneity exists before exposure to neurogenic conditions. The findings provide evidence that GFAP-expressing NSCs are phenotypically and functionally distinct from non-neurogenic astrocytes.

Animals↗

PubMed1997

Expression of CD30 and CD30 ligand in cultured cell lines from human germ-cell tumors.

Embryonal carcinoma (EC) cells are the multipotent stem cells of human teratocarcinomas. EC cell lines isolated from human testicular teratocarcinomas retain pluripotentiality and show cell-surface marker phenotype and growth characteristics similar to those of primate embryonic stem cells. CD30, a member of the tumor necrosis factor superfamily of cytokine receptors, is expressed on the surface of human EC cells, but little is known regarding its function or the expression of its ligand in this context. Northern blot analysis, reverse transcriptase-PCR, and immunoprecipitation were used to study the expression of CD30 ligand and CD30 in cell lines representing multipotent and nullipotent EC as well as yolk sac carcinoma. Antibodies, recombinant CD30-Fc, and recombinant CD30 ligand were used in bioassays to assess the ability of exogenous CD30 ligand to promote the growth of multipotent human EC stem cells. Nullipotent and multipotent human EC cells, but not yolk sac carcinoma, expressed surface CD30, as demonstrated by immunoblotting and immunofluorescence; in multipotent cells, expression was decreased during differentiation induced by retinoic acid. Transcripts for CD30L were found at high levels in a yolk sac carcinoma cell line by Northern analysis and reverse transcriptase-PCR and were present at lower levels in EC cells as well. Immunoprecipitation confirmed expression of CD30 ligand protein in yolk sac carcinoma and in nullipotent embryonal carcinoma. Antibodies with CD30 cross-linking activity failed to promote the growth of multipotent EC cell line GCT 27 X-1. Anti-CD30 ligand antibodies and CD30-Fc both failed to block the promotion of EC cell growth induced by yolk-sac cell culture supernatants or feeder-cell monolayers. CD30 ligand is expressed in cell lines representative of human yolk sac carcinoma and nullipotent embryonal carcinoma. The membrane-bound cytokine may have an autocrine role in human EC stem-cell renewal, but other exogenous factors are required to maintain the growth of multipotent EC cells in vitro.

3T3 Cells↗

PubMed1994

10A1 MuLV induces a murine leukemia that expresses hematopoietic stem cell markers by a mechanism that includes fli-1 integration.

The 10A1 murine leukemia virus induces tumors that lack lineage-specific markers found on myeloid, T-cell, and B-cell lineages. Either erythroid or multipotent stem cells can have this phenotype; therefore we have used fluorescence-activated cell sorter analysis with either multipotent stem cell markers or markers found on lineage-restricted precursors to differentiate between these two possibilities. The results showed that tumors induced by 10A1 expressed multipotent stem cell markers as well as some lineage-restricted precursor markers. To further study the tumor phenotype, we analyzed total RNAs from 10A1-induced tumors by Northern blotting for c-kit, erythropoietin receptor, and T-cell gamma receptor mRNAs. Most of the tumors contained these mRNAs, which are characteristic of early hematopoietic cells. These results are consistent with the hypothesis that 10A1-induced tumor cells are early multipotent hematopoietic stem cells. Southern blot analysis revealed that 14 of 14 10A1-induced tumor cell DNAs examined contained MuLV integrations into the fli-1 gene. The results strongly suggested that promoter insertion into fli-1 is required for tumor formation.

Animals↗

PubMed2002

Prostatic stem cells.

Multipotent cells within the epithelial compartment, together with phenotypically 'plastic' mesenchyma cells (stromal stem cells), provide a repository of protected genetic information from which the structure, stability and functionality of the prostate gland can be maintained. However, mere preservation of cells in a non-dividing state is insufficient to provide the necessary reservoir of information from which the structure and function of the prostate gland can be retained or recreated. Rather, there is a constant dynamic interaction, at the level of information exchange, between stem cells (whether epithelial or mesenchymal) and their surrounding environment (both humoral and physical). Thus, with respect to epithelial stem cells, these reside within environmental 'niches' which allow their controlled and limited proliferation while preserving genomic integrity. Similar 'mesenchymal niches' are also predicted to occur, although not yet identified, thus providing the multipotent source from which the full spectrum of stromal phenotypes might be regenerated. Recent data from studies of the haematopoietic and hepato-biliary systems indicate that the potential scope of stem cells far exceeds the immediate phenotypic complement of those tissues within which they originate, being dependent upon their precise environment as well as their genomic integrity.

Cell Differentiation↗