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Results for “Multipotent Stem Cells”

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PubMed1998

Cell lineage in the developing neural tube.

Acquisition of cell type specific properties in the spinal cord is a process of sequential restriction in developmental potential. A multipotent stem cell of the nervous system, the neuroepithelial cell, generates central nervous system and peripheral nervous system derivatives via the generation of intermediate lineage restricted precursors that differ from each other and from neuroepithelial cells. Intermediate lineage restricted neuronal and glial precursors termed neuronal restricted precursors and glial restricted precursors, respectively, have been identified. Differentiation is influenced by extrinsic environmental signals that are stage and cell type specific. Analysis in multiple species illustrates similarities between chick, rat, mouse, and human cell differentiation. The utility of obtaining these precursor cell types for gene discovery, drug screening, and therapeutic applications is discussed.

Animals↗

PubMed2002

Stem cells and the philosopher's stone.

Stem cell biology is now one of the most exciting and rapidly advancing areas of scientific endeavor. Promises of cures of a wide variety of diseases by specific replacement of damaged or malfunctional tissues by use of totipotent or multipotent stem cells is on the horizon in clinical practice. Stem cells derived from the embryo and from adult tissues have been shown to have extensive potentials for self-renewal and differentiation. In addition, the plasticities of phenotype exhibited in vivo by some of these cell populations challenge the doctrine of irreversibility of cell commitment after particular developmental stages. This brief review considers certain aspects of these recent findings of the many unexpected potentials of stem cells to differentiate into alternative processes, and their potential value for use in tissue reconstruction procedures are prominent areas that require further study. Rigorous investigation of these topics will lead to realistic approaches in the future for stem cell therapy in a variety of human diseases and other clinical problems.

Animals↗

PubMed1992

A Hidden Retinal Regenerative Capacity from the Chick Ciliary Margin is Reactivated In Vitro, that is Accompanied by Down-regulation of Butyrylcholinesterase.

The chicken retina has a capacity to regenerate in vivo, which is restricted up to embryonic day 4 (E4). Here we test the proliferative patterns of dissociated chicken cells from the centre retina or the ciliary margin, including pigmented cells, after their transfer into rotation culture. For central cells in culture, the uptake of [3H]thymidine after a short initial rise decreases similarly to their in ovo counterparts. In contrast, marginal cells that have been shown to regenerate up to E9 into retinotypic stratospheroids re-enter a novel and long-lasting phase of in vitro cell division. We have shown previously that cell types of all nuclear layers are produced. Both observations taken together indicate a pronounced self-renewal of multipotent stem cells. Molecularly, the enzyme butyrylcholinesterase, which in other systems has been shown to mark transitory neuronal cells between proliferation and differentiation, is strongly expressed at the ciliary margin over most of the embryonic period. After these cells are transferred into rotation culture, butyrylcholinesterase is down-regulated. Concomitantly, the neuronal differentiation marker acetylcholinesterase increases. We conclude that the regenerative capacity of the chick retina is not lost at E4, but rather remains hidden in the chicken ciliary margin, since it can be reactivated in vitro at least up to E9. We suggest that butyrylcholinesterase may be linked to the regulation of stem cell activity.

Journal Article↗

PubMed1994

Evidence for engraftment of donor-type multipotent CD34+ cells in a patient with selective T-lymphocyte reconstitution after bone marrow transplantation for B-SCID.

Severe combined immunodeficiencies (SCID), a heterogeneous group of disorders of infancy, are fatal without treatment directed at immunologic reconstitution. Allogeneic bone marrow transplantation (BMT), which is such a treatment presents some unique features in SCID, especially when T-lymphocyte-depleted HLA haploidentical allografts are used. Donor-type T lymphopoiesis, less often B lymphopoiesis, develops, whereas myelopoiesis remains the recipient-type. Little is known about the engrafting cells in this peculiar lymphohematopoietic chimerism and the pathophysiology of the frequent failure of B-lymphocyte reconstitution. To address these issues, we purified CD34+ BM cells from a patient with selective T-lymphocyte reconstitution after HLA haploidentical BMT for B-SCID. Phenotypic analysis of CD34+ cells was performed by flow cytometry, and functional studies of donor- and recipient-type CD34+ cells were performed in vitro. Donor-type CD34+ cells, constituting approximately 2% of the CD34+ cells, were detected; both CD34+ HLA-DR- cells and CD34+ cells coexpressing B-(CD10 and CD19) and T-(CD2 and CD7) lymphocyte-associated cell surface molecules. Donor-type CD34+ cells coexpressing myeloid-associated molecules (CD13, CD14, CD15, and CD33) were undetectable. However, donor-type CD34+ myeloid progenitors could be shown in functional assays. Recipient-type CD34+ cells coexpressing B- and T-lymphocyte- as well as myeloid-associated molecules were detected, but recipient-type CD34+ cells could not be driven into T-lymphocyte differentiation in vitro. These findings provide evidence for engraftment of multipotent stem cells in our patient with B-SCID. Furthermore, the failure of B-lymphocyte reconstitution cannot be explained by lack of donor-type B-lymphocyte progenitors. Donor-type B lymphopoiesis and myelopoiesis are prevented by an unidentified mechanism.

Antibodies, Monoclonal↗

PubMed2001

Differentiation and telomerase activity of human mesenchymal stem cells.

OBJECTIVE: To study the differentiation of human mesenchymal stem cells (MSCs) derived from human fetal bone marrow and observe its telomerase activity. METHODS: MSCs were isolated from fetal bone marrow of the femur followed by cell culture and amplification. In situ hybridization was employed to detect telomerase activity in the MSCs. Subcutaneous implantation of MSCs into nude mice was performed to observe their differentiation potentials 4 weeks after the implantation. RESULTS: Human MSCs were found positive for telomerase activity and they showed the potential to differentiate into such tissue cells as of the bone, cartilage, adipose, skeletal muscle, tendon-like tissue and unmyelinated nerve fiber-like bundles. CONCLUSION: Human MSCs are multipotent stem cells that may differentiate into many types of tissue cells with high levels of telomerase activity.

Journal Article↗

PubMed1989

Promotion of fetal liver engraftment by T cells in a murine semiallogeneic model without graft-versus-host reaction.

Graft failure following transplantation with T cell-depleted bone marrow or with tissue naturally devoid of T cells, such as fetal liver (FL), suggests an important role for T cells in ensuring sustained hematopoietic stem cell engraftment. Whether T cells act by eliminating host residual immune cells--or, alternatively, by helping stem cell growth and differentiation--is still to be determined. The purpose of this study was to analyze the effect of T cell supplementation to the FL graft, using a semiallogeneic murine model where the graft-versus-host reaction is absent. Lethally irradiated C3H/OuJ mice were grafted with 10(6) FL cells from (C3H/OuJ x BALB/c) F1 hybrid mice, with or without 10(6) isogeneic mature T cells (FL and FL + T groups). Recipient animals were then monitored for survival and for hematologic and immune reconstitution. Eight days postgrafting, the number of multipotent stem cells in the spleen was significantly higher in FL + T as compared with FL recipient mice. Addition of T cells to the FL graft provided a faster recovery of hematological parameters and a significant increase in short-term survival (25.5% 6 weeks of survival in the FL group, as opposed to 55.5% 6 weeks of survival in the FL + T group, P less than 0.01). By contrast, immunological functions, as assessed by mitogen responses, were quite similar in both groups of animals. Overall a promoting effect of T cells in early stem cell engraftment was clearly demonstrated in this murine model, where GVHR is absent. These results provide in vivo support for a direct T cell effect on hematopoiesis.

Animals↗

PubMed2005

Characterization of Dicer-deficient murine embryonic stem cells.

Dicer is an RNase III-family nuclease that initiates RNA interference (RNAi) and related phenomena by generation of the small RNAs that determine the specificity of these gene silencing pathways. We have previously shown that Dicer is essential for mammalian development, with Dicer-deficient mice dying at embryonic day 7.5 with a lack of detectable multipotent stem cells. To permit a more detailed investigation of the biological roles of Dicer, we have generated embryonic stem cell lines in which their single Dicer gene can be conditionally inactivated. As expected, Dicer loss compromises maturation of microRNAs and leads to a defect in gene silencing triggered by long dsRNAs. However, the absence of Dicer does not affect the ability of small interfering RNAs to repress gene expression. Of interest, Dicer loss does compromise the proliferation of ES cells, possibly rationalizing the phenotype previously observed in Dicer-null animals. Dicer loss also affects the abundance of transcripts from mammalian centromeres but does so without a pronounced affect on histone modification status at pericentric repeats or methylation of centromeric DNA. These studies provide a conditional model of RNAi deficiency in mammals that will permit the dissection of the biological roles of the RNAi machinery in cultured mammalian cells.

Animals↗

PubMed2000

Nestin-expressing cells in the pancreatic islets of Langerhans.

The pancreatic islets of Langerhans produce several peptide hormones, predominantly the metabolically active hormones insulin and glucagon, which are critical for maintaining normal fuel homeostasis. Some evidence exists that pancreatic endocrine cells turn over at a slow rate and can regenerate in certain conditions. This could be due to the presence of pluripotent cells residing in the pancreas. Recently the intermediate filament protein nestin has been identified to be a marker for a multipotent stem cell in the central nervous system. Given the similarity between the pancreatic islets and neuronal cells, we hypothesized that stem cells expressing nestin might be present in the pancreas. Here we present evidence that a subset of cells in the pancreatic islets express the stem cell marker nestin. These cells might serve as precursors of differentiated pancreatic endocrine cells.

Animals↗

PubMed1984

Evidence for a stem cell common to hematopoiesis and its in vitro microenvironment: studies of patients with clonal hematopoietic neoplasia.

The origin and nature of cells forming the in vitro microenvironment in long-term cultures of human marrow were studied in five patients with clonal myeloproliferative disorders who were heterozygous for glucose-6-phosphatase dehydrogenase (G6PD). The results showed that cells in the adherent stromal layer forming the in vitro microenvironment were derived from the same clonal progenitors involved by the neoplasm in the four patients whose diseases originated in multipotent stem cells. In contrast, stromal cells were derived from normal progenitors in a patient with acute non-lymphocytic leukemia whose clone showed differentiative expression confined to cells in the granulocytic lineage. Mixing experiments demonstrated that the G6PD type displayed by the adherent marrow stromal cells was not obscured by contaminating non-adherent hematopoietic cells or marrow fibroblasts. The data suggest the existence of a pluripotent cell in normal hematopoiesis that gives rise to hematopoietic cells and to their micro-environment.

Adult↗

PubMed1992

Carbohydrate antigens in human lung carcinomas.

Lung carcinomas represent a heterogeneous group of tumours with large variations in the biochemical, clinical, morphological and pathological manifestations. Despite the neuroendocrine features of small cell lung cancer (SCLC), it is today generally accepted that all types of lung cancer emanate from a common endodermally derived multipotent stem cell of the bronchial epithelium. NCAM (neutral cell adhesion molecule) has been shown to be a sensitive marker of SCLC. The presence of NCAM, with the alpha (2,8) polysialic acid units characteristic of embryonal NCAM, in SCLC and in a portion of NSCLC, seems to correlate with the malignant behaviour and prognosis of the tumours, suggesting that NCAM may have a functional role in the clinicopathological manifestations of lung cancer. Fuc-GM1 with 2-hydroxy fatty acids as a characteristic component of the ceramide has been found to be a unique ganglioside of SCLC, detected in the tissues as well as in serum from SCLC patients using specific monoclonal antibodies. Accumulation of sialylated and fucosylated polylactosamine type 2 carbohydrate glycolipid and glycoprotein antigens was found in serum and tissues of lung tumours in accordance with what is described in gastrointestinal carcinomas, and these antigens may be regarded as general carcinoma antigens irrespective of organ. Sialylated and fucosylated type 1 antigens, and gangliosides with NeuAc alpha (2,6)Gal linkage were also accumulated in lung cancer. The human immune system has been found to recognize lung cancer carbohydrate antigens, which might be human lung cancer autoantigens.

Antibodies, Neoplasm↗

PubMed1995

Granzyme B and perforin lytic proteins are expressed in CD34+ peripheral blood progenitor cells mobilized by chemotherapy and granulocyte colony-stimulating factor.

Granzyme B and perforin are cytoplasmic granule-associated proteins used by cytotoxic T lymphocytes and natural killer (NK) cells to kill their targets. However, granzyme B gene expression has also been detected in a non-cytotoxic hematopoietic murine multipotent stem cell line, FDCP-Mix. The objective of the present study was to investigate whether granzyme B and perforin could be expressed in human hematopoietic CD34+ cells and if present, discover what their physiologic relevance could be. The primitive CD34+ human cell line KG1a was investigated first and was found to express granzyme B and perforin. Highly purified hematopoietic stem/progenitor cells were then selected using the CD34 surface antigen as marker. Steady-state bone marrow (BM) CD34+ cells did not contain these proteins. Peripheral blood (PB) CD34+ cells, which had been induced to circulate, were also analyzed. After chemotherapy (CT) and granulocyte colony-stimulating factor (G-CSF) treatment, CD34+ cells strongly expressed mRNAs and proteins of granzyme B and perforin. In contrast, CD34+ cells mobilized by G-CSF alone were negative. Western blot analysis further showed that granzyme B and perforin proteins were identical in CD34+ cells and activated PBLs. Such proteins might be implicated in the highly efficient migration of CD34+ stem/progenitor cells from BM to PB after CT and G-CSF treatment. The cellular adhesion mechanisms involved in the BM homing of CD34+ cells are disrupted at least temporarily after CT. The Asp-ase proteolytic activity of granzyme B on extracellular matrix proteins could be used by progenitor cells for their rapid detachment from BM stromal cells and perforin might facilitate their migration across the endothelial cell barrier.

Antigens, CD34↗

PubMed2005

The origin and development of glial cells in peripheral nerves.

During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating glial cells in a process that parallels gliogenesis from the germinal layers of the CNS. Unlike central gliogenesis, neural crest development involves a protracted embryonic phase devoted to the generation of, first, the Schwann cell precursor and then the immature Schwann cell, a cell whose fate as a myelinating or non-myelinating cell has yet to be determined. Embryonic nerves therefore offer a particular opportunity to analyse the early steps of gliogenesis from transient multipotent stem cells, and to understand how this process is integrated with organogenesis of peripheral nerves.

Animals↗

PubMed1999

Abnormalities of cytokine receptor signalling contributing to diseases of red blood cell production.

The production of erythroid cells is a dynamic and exquisitely regulated process. The mature red cell is only the final phase of a complex but orderly series of genetic events that are initiated at the time a multipotent stem cell becomes committed to expressing the erythroid programme. Aberrations either in the intrinsic generation and/or amplification of functional erythroid cells or in the regulatory influences of microenvironment or cytokines form the basis for a number of blood diseases. In this review we focus upon abnormalities in red blood cell production and discuss how alterations in cytokine regulation of red blood cell production may contribute to these disease processes. We discuss clinical states in which blood red cell numbers are altered, including primary familial and congenital polycythaemia, the myeloproliferative disorder polycythaemia vera, erythroleukaemia, and Diamond-Blackfan anaemia. These disorders are briefly described and evidence supporting a potential role of specific cytokine receptor signalling defects as contributing to these phenotypes is discussed.

Erythropoietin↗

PubMed1992

A strategy for isolation of cDNAs encoding proteins affecting human intestinal epithelial cell growth and differentiation: characterization of a novel gut-specific N-myristoylated annexin.

The human intestinal epithelium is rapidly and perpetually renewed as the descendants of multipotent stem cells located in crypts undergo proliferation, differentiation, and eventual exfoliation during a very well organized migration along the crypt to villus axis. The mechanisms that establish and maintain this balance between proliferation and differentiation are largely unknown. We have utilized HT-29 cells, derived from a human colon adenocarcinoma, as a model system for identifying gene products that may regulate these processes. Proliferating HT-29 cells cultured in the absence of glucose (e.g., using inosine as the carbon source) have some of the characteristics of undifferentiated but committed crypt epithelial cells while postconfluent cells cultured in the absence of glucose resemble terminally differentiated enterocytes or goblet cells. A cDNA library, constructed from exponentially growing HT-29 cells maintained in inosine-containing media, was sequentially screened with a series of probes depleted of sequences encoding housekeeping functions and enriched for intestine-specific sequences that are expressed in proliferating committed, but not differentiated, epithelial cells. Of 100,000 recombinant phage surveyed, one was found whose cDNA was derived from an apparently gut-specific mRNA. It encodes a 316 residue, 35,463-D protein that is a new member of the annexin/lipocortin family. Other family members have been implicated in regulation of cellular growth and in signal transduction pathways. RNA blot and in situ hybridization studies indicate that the gene encoding this new annexin exhibits region-specific expression along both axes of the human gut: (a) highest levels of mRNA are present in the jejunum with marked and progressive reductions occurring distally; (b) its mRNA appears in crypt-associated epithelial cells and increases in concentration as they exit the crypt. Villus-associated epithelial cells continue to transcribe this gene during their differentiation/translocation up the villus. Immunocytochemical studies reveal that the intestine-specific annexin (ISA) is associated with the plasma membrane of undifferentiated, proliferating crypt epithelial cells as well as differentiated villus enterocytes. In polarized enterocytes, the highest concentrations of ISA are found at the apical compared to basolateral membrane. In vitro studies using an octapeptide derived from residues 2-9 of the primary translation product of ISA mRNA and purified myristoyl-CoA:protein N-myristoyltransferase suggested that it is N-myristoylated. In vivo labeling studies confirmed that myristate is covalently attached to ISA via a hydroxylamine resistant amide linkage. The restricted cellular expression and acylation of ISA distinguish it from other known annexins.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed2004

A review: the location, molecular characterisation and multipotency of hair follicle epidermal stem cells.

INTRODUCTION: Recent work has focused on the hair follicle as the main repository of multipotent stem cells in skin, which is a neat model to study the mechanisms regulating the proliferation, migration and final fate of adult stem cells. This review examines the available literature for its location, molecular markers and multipotency. METHODS: Peer-reviewed journals and monographs on the subject were covered. RESULTS: With the application of stem cell-labelling techniques and clonogenicity assay, it is clear that most of the hair follicle stem cells are located at the bulge region, but the base of the hair follicle does contain some clonogenic cells; whether they are stem cells is still unknown. Extensive works have been done in identifying hair follicle stem cells. The potential markers for hair follicle stem cells include: b1-integrin, keratin 19, a6- integrin, CD71, p63, and CD34. Most of these markers are expressed in high levels in hair follicle stem cells, but there is still difficulty in distinguishing hair follicle stem cells from their transitamplifying progeny, and the sorted hair follicle stem cells with these markers are far from pure. As hair follicle stem cells might have been activated after leaving the stem cell niche, the markers for cells in vitro might not be identical to those in vivo. Using double-labelling techniques with BrdU and 3H-Thymidine, and the creation of novel chimera transgenic mice, it was proved that hair follicle stem cells can repopulate wound epidermis, forming epidermis, hair follicles and sebaceous glands, but it contributes little to the epidermis in physiological condition, except the hair follicle. CONCLUSIONS: Slow cycling, label-retaining cells exist at the bulge of the hair follicle, with high proliferative potential and clonogenicity. The putative bulge stem cells can contribute to the epidermis, outer root sheath, inner root sheath, hair shaft and sebaceous gland. However, they still lack certain markers to distinguish bulge stem cells from their progeny, and much work needs to focus on the interrelations between bulge cells and interfollicular keratinocyte stem cells, the relations between bulge cells and dermal papilla mesenchyme cells, and the mechanism of hair growth.

Animals↗

PubMed1995

Organization of the crypt-villus axis and evolution of its stem cell hierarchy during intestinal development.

The small intestinal crypt of the adult mouse represents a model system for studying cell renewal. One or more functionally equivalent stem cells located within the crypt fuel a continuous regeneration of the gut's four principal epithelial cell lineages. These lineages differentiate during a geographically well-organized migration along the crypt-villus axis. This axis does not complete its morphogenetic program until the third postnatal week. We examined the organization of the crypt-villus axis and its stem cell hierarchy in postnatal day 1 (P1) to P28 transgenic mice. These mice contained transcriptional regulatory elements from the liver fatty acid binding protein gene linked to a human growth hormone (hGH) reporter. Adult male and female animals exhibit a striped pattern of hGH accumulation in their villus-associated epithelial cells: vertical coherent bands of wholly hGH-positive epithelial cells derived from a monoclonal crypt and vertical coherent stripes of wholly hGH-negative epithelial cells derived from an adjacent crypt extend to the apical extrusion zone of their common villus. Villus striping develops in a proximal-to-distal wave that extends from the duodenum to the jejunum by P7 and to the ileum by P14. Striping occurs as a result of a loss in the ability to support transgene expression. The decision appears to affect all cells within a stripe, irrespective of their position along the basilar-to-apical axis of a villus, suggesting that it is programmed by the nascent crypt's multipotent stem cell(s). Suppression of transgene expression traverses the crypt-villus axis more rapidly than the rate of epithelial cell migration. The boundary between stripes is very sharp and does not contain cells with transitional levels of the hGH reporter, indicating that the epithelial components of the crypt-villus axis have a higher degree of organization at this stage of development than appreciated previously.

Animals↗

PubMed2002

Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system.

The appropriate control of proliferation of neural precursors has fundamental implications for the development of the central nervous system and for cell homeostasis/replacement within specific brain regions throughout adulthood. The role of genetic determinants in this process is largely unknown. We report the expression of the homeobox transcription factor Emx2 within the periventricular region of the adult telencephalon. This neurogenetic area displays a large number of multipotent stem cells. Adult neural stem cells isolated from this region do express Emx2 and down-regulate it significantly upon differentiation into neurons and glia. Abolishing or, increasing Emx2 expression in adult neural stem cells greatly enhances or reduces their rate of proliferation, respectively. We determined that altering the expression of Emx2 affects neither the cell cycle length of adult neural stem cells nor their ability to generate neurons and glia. Rather, when Emx2 expression is abolished, the frequency of symmetric divisions that generate two stem cells increases, whereas it decreases when Emx2 expression is enhanced.

Animals↗

PubMed1992

Lymphocyte development from stem cells.

Highly enriched pluripotent and multipotent hematopoietic stem cells (HSCs) are isolated from bone marrow and fetal liver as Thy-1loLin-Sca-1+ cells. Pluripotent HSCs express c-kit receptor on their surface, but the generation and proliferation of early fetal HSCs take place in the absence of steel factor. T precursor cells migrate into the fetal thymus by chemotactic mechanism. CD4lo precursors represent a newly defined phase of T-cell development in the thymus between the bone marrow-derived stem cells and the CD4-8- intrathymic precursors. Only fetal, but not adult, HSCs have the capacity to differentiate into V gamma 3+ and V gamma 4+ T cells under the fetal thymic microenvironment, and HSC themselves may lose some of their developmental potential during ontogeny. It is postulated that HSCs are the locus of a complicated but precise developmental clock that may determine both the time-dependent closure of some gene loci (e.g. V gamma 3 and V gamma 4 T cell receptor, and embryonic and fetal globin) and the activation of others (e.g. the N nucleotide insertion machinery).

Animals↗