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Results for “Multipotent Stem Cells”

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PubMed2006

Pluripotency of spermatogonial stem cells from adult mouse testis.

Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages.

Age Factors↗

PubMed1988

The development of hemopoietic cells in response to stromal cells or growth factors is modified by agents that influence ADP-ribosylation.

The in vitro differentiation of multipotent stem cells in long-term marrow cultures can be blocked by treatment with agents that modify cholera toxin induced ADP-ribosylation of proteins. The latter agents also inhibit the growth and development of progenitor cells in soft gels in response to interleukin-3 but have little effect upon the development of progenitor cells that respond to the macrophage colony stimulating factor (CSF-1). Cholera toxin, in the same system, inhibits the development of CSF-1 responsive progenitor cells but has little effect on the development of cells that respond to IL-3. Similarly, progenitor cells that respond to IL-3 are relatively more resistant to pertussis toxin than cells that respond to CSF-1. These data indicate that ADP-ribosylation may be an important post-translational modification of regulatory proteins concerned with hemopoietic cell differentiation and growth in response to stromal cells or growth factors.

Adenosine Diphosphate↗

PubMed1983

Cyclic hematopoiesis: disorders of primitive hematopoietic stem cells.

Utilizing both in vivo and in vitro techniques, a great deal of information has been obtained on the structure and regulation of the hematopoietic cell lineages. A number of hematopoietic stem cells and regulators have now been well characterized and their possible physiologic relevance at least in part established. More recently, new "alternative" or primitive stem cells have been described which may provide important insights into the nature of hematopoietic regeneration and regulation. These include late CFUs, high proliferative potential colony-forming cells, colony-forming unit diffusion chamber and both bipotent and blast colonies assayed in in vitro culture systems. Regulators active at these stem cell levels are also under study and in large part appear to be produced by monocytes or lymphocytes. Cyclical hematopoiesis can be viewed as a genetic abnormality at the multipotent stem cell level with defective cell production. At present however, details of the defect await further investigation possibly including an evaluation of the role of primitive stem cells and their regulators.

Animals↗

PubMed2006

Developmental pathways and specification of intrapulmonary stem cells.

Tissues have the capacity to maintain a homeostatic balance between wear-and-tear and regeneration. Repair of non-lethal injury also activates cell proliferation to repopulate the injured sites with appropriate cell types and to restore function. Although controversial, the source of the material appears to be at least partly from pools of unique, multipotent stem cells that reside in specialized locations referred to as "niches." Molecular interactions between the niche and the intracellular factors within stem cells are crucial in maintaining stem cell functions, particularly the balance between self-renewal and differentiation. Many of the mediators of the stem cell-niche interactions are similar or identical to those that control developmental pathways during organogenesis. In this review, we present a systematic discussion and evaluation of the relevant literature with a focused emphasis on three primary signaling pathways, WNT, SHH and BMP with potentially overlapping roles during both development and stem cell maintenance.

Humans↗

PubMed2005

IL-6 blocks a discrete early step in lymphopoiesis.

Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis. These effects are mediated at least in part by elevated levels of interleukin 6 (IL-6). Here, we show the lymphopoiesis block in SHIP-/- mice is due to suppression of the lymphoid lineage choice by uncommitted progenitors. The suppression can be reproduced in vitro with recombinant IL-6, and IL-6 acts directly on hematopoietic progenitors. The block is partially overcome in SHIP-/- IL-6-/- double-deficient animals. IL-6 does not suppress but actually enhances proliferation of lymphoid-committed progenitors, indicating the IL-6 target cells are hematopoietic stem cells or multipotent progenitors. The findings suggest a mechanism for the lymphopenia that accompanies proinflammatory diseases.

Animals↗

PubMed1993

Segregation of cell lineage in the neural crest.

Following neurulation, neural crest cells emerge from the neural tube and undergo extensive migrations. At the onset of migration, multipotent stem cells exist within the neural crest population. Eventually, these assume one of a number of possible fates, ranging from neurons and glia of the peripheral nervous system to pigment cells and cells of the facial skeleton. Neural crest cells follow migratory pathways and differentiate into derivatives that often are characteristic of their axial level of origin. Based on their stereotyped patterns of migration, limited intermixing and distinct homeobox-gene codes, some populations of neural crest cells may have a rostrocaudal regional identity imprinted prior to their emigration.

Animals↗

PubMed2006

Neuropeptide Y in the olfactory microvillar cells.

This paper examines a possible role of microvillar cells in coordinating cell death and regeneration of olfactory epithelial neurons. The olfactory neuroepithelium of mammals is a highly dynamic organ. Olfactory neurons periodically degenerate by apoptosis and as a consequence of chemical or physical damage. To compensate for this loss of cells, the olfactory epithelium maintains a lifelong ability to regenerate from a pool of resident multipotent stem cells. To assure functional continuity and histological integrity of the olfactory epithelium over a period of many decades, apoptosis and regeneration require to be precisely coordinated. Among the factors that have been implicated in mediating this regulation is the neuropeptide Y (NPY). Knockout mice that lack functional expression of this neurogenic peptide show defects in embryonic development of the olfactory epithelium and in its ability to regenerate in the adult. Here we show that, in postnatal olfactory epithelia, NPY is exclusively expressed by a specific population of microvillar cells. We previously characterized these cells as a novel type of putative chemosensory cells, which are provided with a phosphatidyl-inositol-mediated signal transduction cascade. Our findings allow for the first time to suggest that microvillar cells are involved in connecting apoptosis to neuronal regeneration by stimulus-induced release of NPY.

Animals↗

PubMed1998

Multiple routes to astrocytic differentiation in the CNS.

Ciliary neurotrophic factor (CNTF) acts instructively to switch multipotent stem cells of the CNS to an astrocytic fate. Here we show that CNTF causes activation of janus kinase-signal transducers and activators of transcription and mitogen-activated protein kinase (MAPK) pathways with differential kinetics in these cells. Inhibition studies indicate that activation of the MAPK pathway is required early in the differentiation process, whereas activation of signal transducer and activator of transcription (STAT) proteins is required for commitment to an astrocytic fate. Bone morphogenetic proteins have also been shown to cause astrocytic differentiation but do not cause STAT activation or astrocytic differentiation in fibroblast growth factor 2-expanded fetal stem cells used here. These results show that there are two distinct routes to initiate astrocytic commitment in multipotent CNS precursors.

Animals↗

PubMed1994

Growth factors and the molecular control of haematopoiesis.

In the absence of appropriate growth factors, for example interleukin-3 or GM-CSF, cultured bone marrow stem cells die by a process known as apoptosis or programmed cell death. Apoptosis may occur in vivo when concentrations of specific growth factors are limiting and may be a means of regulating cell numbers. Growth factors are also essential for proliferation of bone marrow stem cells but differentiation can occur, provided there is a survival stimulus in the absence of growth factors. Combinations of growth factors may be synergistic in stimulating the survival and proliferation of multipotent stem cells. Although neither stem cell factor, nor GM-CSF alone can significantly induce the proliferation of stem cells, the combination induces the proliferation of these cells. Committed progenitor cells such as granulocyte-macrophage colony-forming cells, however, are stimulated to proliferate by GM-CSF alone, while stem cell factor in combination with GM-CSF results in only a slight additive effect. To date, most research has concentrated on the growth stimulatory factors. GM-CSF has an important role in the reversal of chemotherapy-induced myelosuppression in cancer patients and in other bone marrow disorders. A number of growth inhibitory molecules have now been identified, such as macrophage inhibitory protein-1 alpha. In the future, it is possible that improvements in cure rates may be achieved in cancer patients by combining the growth inhibitory factors with the stimulatory factors. Inhibitory factors may be given before chemotherapy to prevent toxicity and stimulatory factors may be given afterwards to treat neutropenic patients.

Cell Differentiation↗

PubMed2004

Umbilical cord blood stem cells can expand hematopoietic and neuroglial progenitors in vitro.

The ability of hematopoietic tissue-derived adult stem cells to transdifferentiate into neural progenitor cells offers an interesting alternative to central nervous system (CNS)- or embryonic-derived stem cells as a viable source for cellular therapies applied to brain regeneration. Umbilical cord blood (CB) due to its primitive nature and it unproblematic collection appears as a promising candidate for multipotent stem cell harvest. We developed a negative immunomagnetic selection method that depletes CB from hematopoietic lineage marker-expressing cells, hence isolating a discrete lineage negative (LinNeg) stem cell population (0.1% of CB mononucleated cell [MCN] population). In liquid culture supplemented with thrombopoietin, flt-3 ligand, and c-kit ligand (TPOFLK), CB LinNeg stem cells could expand primitive nonadherent hematopoietic progenitors (up to 47-fold) and simultaneously produce slow-dividing adherent cells with neuroglial progenitor cell morphology over 8 weeks. Laser scanning confocal microscopy analysis identified these adherent cells to express glial fibrillary acidic protein (GFAP). Gene expression analysis showed upregulation of primitive neuroglial progenitor cell markers including, GFAP, nestin, musashi-1, and necdin. ELISA quantification of liquid culture supernatant revealed the in vitro release of transforming growth factor beta-1 (TGFbeta1), glial cell line-derived neurotrophic factor (GDNF) suggesting their contribution to CB LinNeg stem cell transdifferentiation into neuroglial progenitors. Our study supports that a single CB specimen can be pre-expanded in TPOFLK to produce both primitive hematopoietic and neuropoietic progenitors, hence widening CB clinical potential for cellular therapies.

Biomarkers↗

PubMed1988

Philadelphia-positive acute leukemia: lineage promiscuity and inconsistently rearranged breakpoint cluster region.

Six patients with Philadelphia-positive (Ph1+) acute nonlymphocytic leukemia (ANLL) were studied by morphological, immunological, cytogenetic, and molecular techniques. Seven Ph1+ acute lymphocytic leukemia (ALL) cases were also studied for comparison. Three of ANLL cases were classified in M1, M2, and M4 groups of the FAB nomenclature, while the three other cases do not fit with any FAB subgroup and are described as M0. Immunophenotypical marker studies, double immunolabeling, and combined immunological and cytogenetic studies of metaphases showed that these ANLL expressed several lineage differentiation antigens. Rearrangements of immunoglobulin heavy chain gene (C mu) were detected in the six ANLL cases and in the seven ALL cases studied, as well as, in most cases, rearrangement of T cell receptor beta chain genes and/or T cell rearranging gamma genes. The results favored the assumption that the Ph1 translocation originated from a multipotent stem cell in Ph1+ ANLL. A common t(9;22) translocation was found in all cases, and additional chromosomal abnormalities were present in the six ANLL cases and in five of the seven ALL cases. Molecular studies of bcr gene configuration and c-abl transcription allowed two groups of Ph1+ ANLL to be distinguished. Three cases had bcr rearrangement and c-abl mRNA expression comparable to those reported in Ph1+ chronic myeloid leukemia, while three others had not detectable bcr rearrangement and a 7.2-7.5 kb c-abl mRNA. The existence of Ph1+ ALL with and without classical bcr rearrangement was confirmed.

Adolescent↗

PubMed2002

Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons.

Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.

Animals↗

PubMed1998

Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also relatively resistant to chemotherapy and the disease is difficult to cure using conventional therapeutic routes. CML is associated with increased abl oncogene protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that these aberrant responses to MIP-1alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts v-abl PTK and grown at the restrictive temperature for PTK activity the cells were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5-fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree of protection from these agents. At the permissive temperature for abl PTK, the cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment neither induced growth inhibition nor protected the cells from cytotoxic drug induced cell death. This lack of response to MIP-1alpha was not due to receptor down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases in cytosolic Ca2+ levels were abrogated by switching cells to the permissive temperature for Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1alpha occurs as a direct consequence of abl PTK activity and involves desensitisation of signal transduction events stimulated by MIP-1alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.

Calcium↗

PubMed1999

Lineage commitment and maturation of epithelial cells in the gut.

The dynamic concepts of gut epithelial cell populations which heralded the era of modern gut cell biology have been generally substantiated by recent studies and are still being correlated with functional properties. Multipotent stem cells are anchored in specific locations along the gut epithelium where decisions concerning proliferation and differentiation/migration pathways are made. Stem cells give rise to lineage precursors which transform into transit cells and sequentially express lineage specific features during their differentiation program. Morphologically and functionally mature cells along the gut epithelium are dynamically heterogeneous. 1) The squamous lineage of the esophagus forms a stratified epithelium which has an average turnover time of about 7. 5 days. 2) In the stomach, the oxyntic pit-gland unit includes pit, zymogenic and parietal cells which respectively migrate outwards, inwards, and in both directions; their turnover times average 3, 194 and 54 days, respectively. 3) The mucous units of the pyloric antrum are populated by pit cells which migrate outwards and gland cells which migrate inwards; their turnover times are about 3 and 1-60 days, respectively. 4) In the crypt-villus units of the small intestine, while both absorptive and goblet cells migrate outwards and for each the turnover time is about 3 days, Paneth cells migrate inwards and their turnover time is about 15 days. 5) In the crypts of the descending colon, both vacuolated-columnar and goblet cells migrate outwards and for each the turnover time is about 5 days. The ascending colon has an additional cell type called deep crypt secretory cells which migrate inwards and their turnover time is about 14-21 days. Finally, while the factors maintaining the gut epithelium in a steady state remain to be elucidated, this epithelium represents a remarkable system for studying the biological features of stem cells and their hierarchies.

Animals↗

PubMed2001

Stem cells and the regulation of proliferation, differentiation and patterning in the intestinal epithelium: emerging insights from gene expression patterns, transgenic and gene ablation studies.

Tissues that undergo self-renewal such as the skin, the haematopoeitic system and the intestine are all maintained and renewed by a small group of multipotent stem cells. The stem cells of the intestinal epithelium are located in the crypts and give rise to its four main lineages located mainly in the finger like projections- the villi. An increasing number of genes are now being identified as either being necessary for or involved in the maintenance of intestinal stem cells and regulating differentiation along the crypt-villus axis. These developmental regulatory genes include among others, Tcf-4, Cdx-1 Fkh6, HFH11 and Nkx2-3. Other genes such as the integrins, and Indian hedgehog (Ihh) also affect function of the progenitor cells of the intestinal epithelium. This mini-review will focus on the more recent data on expression patterns of genes in the intestinal epithelium and the direct or indirect effects of their ablation on proliferation and differentiation.

Animals↗

PubMed2004

Nonmuscle stem cells fail to significantly contribute to regeneration of normal muscle.

Whole, normal extensor digitorum longus muscles (EDL) were orthtopically transplanted into transgenic mice, expressing nuclear localing beta-galactosidase (nlsbeta-gal) under control of a muscle-specific promoter, in order to determine the extent to which nonmuscle derived, multipotent stem cells (which under experimental conditions exhibit myogenic potential) are spontaneously recruited from distal, nonmuscle organs to participate in the graft's regeneration. The host's contribution to the graft's regeneration was determined by evaluating the number and distribution of beta-gal positive myonuclei in regenerated grafts. Fibers with beta-gal positive nuclei accounted for approximately 1% of the long-term (28- and 56-day) graft's myofibers. All were confined to the graft's periphery, adjacent to host's muscles. Failure to find myofibers with beta-gal positive nuclei across the revascularized graft's girth demonstrated that there was no meaningful recruitment of nonmuscle stem cells from distal host organs, which must arrive at the graft via the circulation. Rather, stem cells residing in the graft at the time of transplantation accounted for approximately 99.9% of the regenerated graft's myonuclei, with a minor contribution from the surrounding host muscles' myosatellite cells (that occurred when the epimysia of graft or host muscles were damaged during transplantation). The significance of these findings to gene therapy for Duchenne muscular dystrophy is discussed.

Animals↗

PubMed1995

Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.

The flk2 receptor tyrosine kinase has been implicated in hematopoietic development. Mice deficient in flk2 were generated. Mutants developed into healthy adults with normal mature hematopoietic populations. However, they possessed specific deficiencies in primitive B lymphoid progenitors. Bone marrow transplantation experiments revealed a further deficiency in T cell and myeloid reconstitution by mutant stem cells. Mice deficient for both c-kit and flk2 exhibited a more severe phenotype characterized by large overall decreases in hematopoietic cell numbers, further reductions in the relative frequencies of lymphoid progenitors, and a postnatal lethality. Taken together, the data suggest that flk2 plays a role both in multipotent stem cells and in lymphoid differentiation.

Animals↗

PubMed2005

Wnt control of stem cells and differentiation in the intestinal epithelium.

The intestinal epithelium represents a very attractive experimental model for the study of integrated key cellular processes such as proliferation and differentiation. The tissue is subjected to a rapid and perpetual self-renewal along the crypt-villus axis. Renewal requires division of multipotent stem cells, still to be morphologically identified and isolated, followed by transit amplification, and differentiation of daughter cells into specialized absorptive and secretory cells. Our understanding of the crucial role played by the Wnt/beta-catenin signaling pathway in controlling the fine balance between cell proliferation and differentiation in the gut has been significantly enhanced in recent years. Mutations in some of its components irreversibly lead to carcinogenesis in humans and in mice. Here, we discuss recent advances related to the Wnt/beta-catenin signaling pathway in regulating intestinal stem cells, homeostasis, and cancer. We emphasize how Wnt signaling is able to maintain a stem cell/progenitor phenotype in normal intestinal crypts, and to impose a very similar phenotype onto colorectal adenomas.

Animals↗