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PubMed1997

The adult rat hippocampus contains primordial neural stem cells.

Adult-derived hippocampal progenitors generate neurons, astrocytes, and oligodendrocytes in vitro and following grafting into the adult brain. Although these progenitors have a considerable capacity for in vitro self renewal, it is not known if each lineage is generated by separate committed precursors or by multipotent stem cells. By genetic marking, we have followed individual cells through the process of proliferative expansion, commitment, and differentiation. All three lineages are generated by single marked cells and the relative proportions of each lineage can be strongly influenced by environmental cues. Differentiation is accompanied by a characteristic progression of lineage-specific markers and can be potentiated by retinoic acid, elevated cyclic AMP, or neurotrophic factors. The ability to genetically mark and clone normal diploid hippocampal progenitors provides the first definitive evidence that multipotent neural stem cells exist outside of the adult striatal subventricular zone and supports the hypothesis that FGF-2-responsive neural stem cells may be broadly distributed in the adult brain.

Animals↗

PubMed2004

Side population cells in human and mouse epidermis lack stem cell characteristics.

Cells that exclude Hoechst 33342 have been found in many tissues, and common for these cells is a characteristic profile when analysed by flow fluorimetry (sp, side population). Since sp cells in some cases function as multipotent stem cells, we investigated whether the epidermis contains sp cells (Esp cells) and whether these cells were epidermal stem cells. We show that mouse and human epidermis contain sp cells, and, to identify the origin of these cells, we tested the expression of several marker genes. We find that Esp cells constitute a subpopulation of the alpha6 integrin-positive basal cells of the mouse epidermis. They are positive for sca-1 and negative for MHC class II and Flk1. They are not identical to the label-retaining population but are cycling cells in the mouse epidermis. Keratinocytes positive for sca-1 are located outside the stem cell containing bulge area of the mouse hair follicle. Forty-four human skin samples were analysed, and Esp cells were found at frequencies ranging from 0.01% to 5.39%, independently of age and body site. Human Esp cells did not express particular high levels of beta1 integrin. However, they expressed the half transporter ABCG2 and we identified high expression of this marker in the secretory duct epithelium of the sweat glands whereas low expression was found in the basal layer of the epidermis.

3T3 Cells↗

PubMed1983

Hemopoiesis in spleen and bone marrow cultures.

Long-term cultures established from spleen cells were compared to those established from bone marrow cells for their ability to maintain hemopoiesis as measured by the presence of hemopoietic progenitor cells (in vitro CFU) and multipotent stem cells (CFU-S). The frequency of both in vitro CFU and CFU-S increased dramatically during the first 2 weeks in the spleen cultures. Following this early peak of activity, the number of progenitors and stem cells declined to undetectable levels by week 6 of culture. During this short phase of hemopoiesis, large amounts of GM-CSF could be detected in the supernatant of the spleen cultures. In contrast, bone marrow cultures did not share this early peak of hemopoiesis; however, they maintained activity for much longer periods of time than did the spleen cultures. When spleen stem cells were seeded onto functional bone marrow adherent cells, spleen-derived in vitro CFU were maintained well beyond week 6 of culture. Spleen cultures established from athymic nu/nu mice showed a greatly reduced ability to support hemopoiesis while those from S1/S1d mice maintained GM-CFU as well as cultures from normal mice.

Animals↗

PubMed1984

Interstitial cell migration in Hydra attenuata. I. Quantitative description of cell movements.

The interstitial cell system of hydra contains multipotent stem cells which can form at least two classes of differentiated cell types, nerves and nematocytes. The amount of nerve and nematocyte production varies in an axially dependent pattern along the body column. Some interstitial cells can migrate, which makes it conceivable that this observed pattern of differentiation is not the result of regionally specified stem cell commitment, but rather arises by the selective movement of predetermined cells to the correct site prior to expression. To assess this latter possibility quantitative information on the dynamics of interstitial cell migration was obtained. Epithelial hydra were grafted to normal animals in order to measure (1) the number of cells migrating per day, (2) the location of these cells within the host tissue, and (3) the axial directionality of this movement. Tissue properties such as axial position and the density of cells within the interstitial spaces of the host were also tested for their possible influence on migration. Results indicate that there is a considerable traffic of migrating interstitial cells and this movement has many of the characteristics necessary to generate the position-dependent pattern of nerve differentiation.

Animals↗

PubMed1985

Growth regulation of the interstitial cell population in hydra. I. Evidence for global control by nerve cells in the head.

The interstitial cells of hydra form a multipotent stem cell system, producing terminally differentiated nerve cells and nematocytes during asexual growth. Under well-fed conditions the interstitial cell population doubles in size every 4 days. We have investigated the possible role of nerve cells in regulating this behavior. Nerve cells are normally found in highest concentrations in the head region of hydra, while interstitial cells are primarily located in the body column. Our experimental approach was to construct, by grafting, animals in which the density of nerve cells varied in (1) the head region, or (2) the body column. The growth of the interstitial cell population was then measured in these hydra. The results indicate that differences in head nerve cell density are closely correlated with how fast the interstitial cell population increases in size. Variations in the level of either nerve cells or interstitial cells in the body column showed no such correlation. These findings suggest the existence of a signaling mechanism in the head region. This signal, which is a function of the density of head nerve cells, emanates from the head tissue and exerts global control on the growth of the interstitial cell population in the body column.

Animals↗

PubMed1997

Gene therapy for AIDS.

The absence of effective treatments makes AIDS one obvious candidate among the infectious diseases which might be treated by somatic gene therapy. Since HIV1 predominantly infects cells of the haematopoietic system, multipotent stem cells or more mature CD4+ cells constitute potential targets for the introduction of a foreign antiviral gene that will inhibit HIV1 replication and/or spread. Reimplantation of the genetically-modified cells into HIV-infected patients should theoretically allow the repopulation of the host with HIV1-resistant CD4+ cells that might be able to control virus propagation in vivo. Alternatively, increased knowledge of the immunological mechanisms involved in the control of virus infection and propagation has led to the development of different strategies to augment host anti-HIV1 cytotoxic T lymphocyte responses in an effort to prevent virus spread and, hence, the onset of AIDS. While the therapeutic value of such approaches still remains unknown, these experimental treatments hold real promise that require thorough clinical evaluation.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Simian virus 40 T antigen-induced amplification of pre-parietal cells in transgenic mice. Effects on other gastric epithelial cell lineages and evidence for a p53-independent apoptotic mechanism that operates in a committed progenitor.

Gastric units in the glandular epithelium of the mouse stomach contain several types of continuously renewing epithelial cells. Acid-producing parietal cells are derived from a multipotent stem cell that also gives rise to mucus-producing pit cells and pepsinogen- and intrinsic factor-producing zymogenic cells. We used nucleotides -1035 to +24 of the mouse H+/K(+)-ATPase beta subunit gene (H+/K(+)-ATPase beta subunit-1035 to +24) to examine the consequences of expressing simian virus 40 T antigen (SV 40 TAg) in the normally rare, nonproliferating, short-lived pre-parietal cell progenitor. Light and electron microscopic morphologic studies plus multilabel immunohistochemical analyses of postnatal day (P) 14-80-day transgenic mice revealed that SV40 TAg produces a 50-70-fold amplification of pre-parietal cells which become the predominant cell type in gastric units. Differentiation to mature parietal cells is blocked, resulting in hypochlorhydria and an associated systemic iron deficiency. SV40 TAg-induced pre-parietal proliferation is accompanied by apoptosis. Examination of adult transgenic mice homozygous for p53 wild type or p53 null alleles established that the apoptosis occurs through a p53-independent pathway. H+/K(+)-ATPase beta subunit -1035 to +24/SV40 Tag is not expressed during differentiation of the zymogenic lineage. Nonetheless, P28-P80 transgenic mice exhibit an apparent block in the conversion of pre-zymogenic to zymogenic cells. This block appears to be quite specific: conversion of preneck to neck cells and neck to pre-zymogenic cells is not affected. Comparison of normal and transgenic mice that are p53+/+ or p53-/- confirmed that the loss of mature zymogenic cells is not dependent upon p53. Although H+/K(+)-ATPase beta subunit -1035 to +24 is not active in pit cell progenitors or their differentiated descendants, there is a 2-3-fold increase in mature pit cells in transgenic animals. Our findings (i) demonstrate an approach for amplifying and characterizing pre-parietal or other progenitor cell populations in gastric units, (ii) reveal an SV40 TAg-inducible, p53-independent apoptotic mechanism that operates in a committed epithelial progenitor cell, and (iii) provide a transgenic mouse model for defining factors that may mediate progression through specific points in the differentiation programs of the parietal and zymogenic cell lineages or that may influence decisions about allocation to the pit cell lineage.

Animals↗

PubMed2001

Requirement of Math1 for secretory cell lineage commitment in the mouse intestine.

The mouse small intestinal epithelium consists of four principal cell types deriving from one multipotent stem cell: enterocytes, goblet, enteroendocrine, and Paneth cells. Previous studies showed that Math1, a basic helix-loop-helix (bHLH) transcription factor, is expressed in the gut. We find that loss of Math1 leads to depletion of goblet, enteroendocrine, and Paneth cells without affecting enterocytes. Colocalization of Math1 with Ki-67 in some proliferating cells suggests that secretory cells (goblet, enteroendocrine, and Paneth cells) arise from a common progenitor that expresses Math1, whereas absorptive cells (enterocytes) arise from a progenitor that is Math1-independent. The continuous rapid renewal of these cells makes the intestinal epithelium a model system for the study of stem cell regeneration and lineage commitment.

Alleles↗

PubMed1996

Cardiac sodium channels expressed in a peripheral neurotumor-derived cell line, RT4-B8.

RT4-B is one of several cell lines derived from a multipotent stem cell line, RT4-AC, which originated from a rat peripheral neurotumor. Based on Northern blot and ribonuclease protection experiments, RT4-B8 cells have been proposed to express rat cardiac Na channel mRNA as the major isoform. We report here direct electrophysiological evidence that the expressed voltage-gated Na channels in the RT4-B8 cell line are of the cardiac phenotype with no evidence for subpopulations expressing other Na channel isoforms. Current activation half point (conductance) was -41 +/- 5 mV (n = 7) and the steady-state voltage-dependent availability half point was -89 +/- 1 mV. As expected for cardiac Na channels, the half concentration of block for tetrodotoxin block was 0.74 microM, for saxitoxin (STX) was 0.15 microM, and for the class 2B divalent cation Cd2+ was 67 microM. Block was well described by single-site dose-response relationships with no indication of a subpopulation with "neuronal" affinity. Single-channel conductance (140 mM Na+) was 10 pS and predicted the average number of channels open at peak Na current to be 3 channels/microns2. [3H]STX binding data were also consistent with a single population of low-affinity STX binding sites and predicted channel density to be 11 sites/microns2. No inwardly or outwardly rectifying K or Ca currents were detected electrophysiologically, although in some cells a small time-independent Cl current was detected. Reverse transcription-polymerase chain reaction of mRNA isolated from RT4-B8 cells demonstrated the presence of rat cardiac (rH1) and brain IIa alpha-subunit mRNA, as well as mRNA for the Na channel beta 1-subunit. Northern blot analysis confirmed the predominance of the rat cardiac Na mRNA compared with brain IIa. The beta 1-subunit mRNA levels were significantly lower than those detected in rat brain and heart mRNA but were comparable to the low level of beta 1-subunit mRNA detected in isolated rat ventricular myocytes.

Animals↗

PubMed1981

Regulation of interstitial cell differentiation in Hydra attenuata. VI. Positional pattern of nerve cell commitment is independent of local nerve cell density.

The interstitial cell of hydra is a multipotent stem cell, which produces nerve cells as one of its differentiated cell types. The amount of interstitial cell commitment to nerve differentiation varies in an axially dependent pattern along the body column. The distribution of nerve cell density has the same equivalent axial pattern. These facts have led to speculation that the regulation of nerve cell commitment is dictated by the nerve cell density. We examined this question by assaying interstitial cell commitment behaviour in 2 cases where the normal nerve cell density of the tissue had been perturbed: (1) in epithelial hydra in which no nerve cells were present; and (2) in hydra derived from regenerating-tip isolates in which the nerve density was increased nearly 4-fold. We found no evidence of regulation of nerve cell commitment in response to the abnormal nerve cell densities. However, the typical axial pattern of nerve commitment was still obtained in both sets of experiments, which suggests that interstitial cell commitment to nerve differentiation is dependent on some parameter of axial location that is not associated directly with the local nerve cell density.

Animals↗

PubMed1993

Differentiation and growth modulation of myeloid leukemia cells by the protein kinase C activating agent bryostatin-1.

Bryostatin-1 (Bryo), a macrocyclic lactone of the sea water bryozoan Bugula neritina, is a potent activator of protein kinase C and was found to exhibit antineoplastic activity in several systems. We studied the effect of Bryo on differentiation and growth modulation of human myeloid leukemia cell lines and freshly explanted blood cells from patients with myeloid leukemia. Alterations at the molecular level and phenotypic changes triggered by Bryo were similar, but not identical, to those induced by phorbol esters. Bryo was able to inhibit cellular proliferation as evidenced by [3H]-thymidine uptake and induced morphological changes associated with monocytic differentiation. In studies using continuous cell lines, the glucocorticoid dexamethasone was unable to prevent the Bryo-induced growth inhibition or the induced phenotypic changes. However, in fresh myeloid blood cells dexamethasone attenuated these Bryo-triggered effects. Our own data taken together with reports from the literature reviewed here suggest the following conclusions: (i) Bryo, while lacking tumor promoting activity, is able to induce differentiation in maturation arrested leukemia cells; (ii) it exhibits selective antiproliferative properties in normal or malignant hematopoietic cells and supports growth of multipotent stem cells. These features might qualify Bryostatin-1 as a potential candidate for promising research and possibly for future clinical applications.

Antineoplastic Agents↗

PubMed1987

A re-evaluation of the function of the bursa of Fabricius.

We will briefly outline mammalian B cell ontogeny to provide a comparison with the avian model. The earliest defined stage of mammalian B cell development is the pre-B cell (itself derived from a multipotent stem cell) which expresses heavy chains within the cytoplasm and is a large, rapidly dividing cell. This cell drops out of division, reduces in size and, over about 24 hours, rearranges Ig light chain V region gene. As a consequence of light chain rearrangement and expression, intact IgM is expressed on the cell surface and the cell leaves the bone marrow as a small virgin B lymphocyte with the capacity to respond to antigen (Opstelten and Osmond 1983). This pathway occurs throughout the life of the animal and so there is constant production of B cells from the bone marrow which are recently derived from sIg- precursors, which have, in turn, recently rearranged their Ig V region genes. Thus there is a constant influx of new V region gene combinations into the peripheral mammalian B cell pool. Furthermore, the mammalian B cell repertoire is very large with estimated germ line diversity approaching 5 X 10(7) as a consequence of various germ-line V region recombinations (Honjo 1983). The pre-bursal stem cell is present in the periphery of the embryo from before day 8 to about day 16 - 17 of embryonation. Most colonisation of bursal follicles probably occurs prior to day 13. Individual bursal follicles are populated by a low number (2-3) of precursor cells. These rapidly become committed for the expression of particular V region genes, probably as a consequence of productive V region recombination. This recombination is restricted to the embryo and may not require the bursal microenvironment for its induction. The available germ-line repertoire of heavy and light chain V region in the chicken is very limited and little diversity can be generated from this initial recombination event (see Weill et al 1986). By day 12 of embryonation, sIg+ cells are present in the bursa and from this time sIg+ cells rapidly divide within the medulla of the bursal follicle. By about day 18 of embryonation, there are no pre-bursal cells in the periphery and sIg+ cells begin to seed from the bursa. It is from about this time that the cortex appears within the bursal follicle and it is tempting to suggest that cells migrate from the medulla to the cortex where further cell division occurs prior to export into the periphery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

Isolation and characterization of the cDNA for mouse neutrophil collagenase: demonstration of shared negative regulatory pathways for neutrophil secondary granule protein gene expression.

A characteristic of normal neutrophil maturation is the induction of secondary granule protein (SGP) mRNA expression. Several leukemic human cell lines mimic normal morphologic neutrophil differentiation but fail to express SGPs, such as lactoferrin (LF) and neutrophil gelatinase (NG). In contrast, two murine cell lines (32D C13 and MPRO) are able to differentiate into neutrophils and induce expression of LF and NG. Therefore, to study the normal regulation and function of these genes, the corresponding murine homologs must be isolated. Using cDNA representational difference analysis (RDA) to compare a committed myeloid progenitor cell line (EPRO) with the multipotent stem cell line from which it was derived (EML), we isolated a fragment bearing homology to human neutrophil collagenase (hNC). Here, we describe the cloning and characterization of a full-length ( approximately 2 kb) clone that exhibits nearly 65% nucleotide and 73% amino acid identity to hNC. Ribonuclease protection analysis (RPA) of the tissues and cell lines shows that mouse NC (mNC) is expressed only in cell lines exhibiting neutrophilic characteristics, further confirming its identity as the mouse homolog of hNC. Furthermore, we have demonstrated a shared negative regulatory pathway for this and other SGP genes. We have previously shown that CCAAT displacement protein (CDP/cut) binds to a specific region of the LF promoter, and overexpression of CDP blocks G-CSF-induced upregulation of LF gene expression in 32D C13 cells. We show here that in these cells, upregulation of both NC and NG is also blocked. CDP is thus the first identified transcription factor that is a candidate for mediating the shared regulation of neutrophil SGP protein genes.

Amino Acid Sequence↗

PubMed2000

Fetal and adult human CNS stem cells have similar molecular characteristics and developmental potential.

The mammalian central nervous system (CNS) contains multipotent stem cells that develop into neurons, astrocytes and oligodendrocytes. Our current data show that fetal and adult human CNS stem cell isolates display similar proliferation kinetics, differentiate into three major cell types of the nervous system and express similar sets of regulatory genes. However, each individual CNS stem cell isolate could be distinguished by its specific gene expression and developmental potential.

Astrocytes↗

PubMed2006

Stem cell properties of human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Stem cells have been used for regenerative therapies in various fields. The proportion of cells that possess stem cell properties in human periodontal ligament (PDL) cells is not yet well understood. In this study, we quantitatively characterized human PDL cells to clarify their stem cell properties, including self-renewal, multipotency, and stem cell marker expression. MATERIAL AND METHODS: PDL cells were obtained from extracted premolar or wisdom teeth, following which a proliferation assay for self-renewal, a differentiation assay for multipotency, immunostaining for STRO-1, and fluorescence-activated cell sorter (FACS) analysis for stem cell markers (including CD105, CD166, and STRO-1) were performed. RESULTS: Approximately 30% of 400 PDL cells were found to possess replicative potential and formed single-cell colonies, and 30% of these colonies displayed positive staining for STRO-1, 20% differentiated into adipocytes and 30% differentiated into osteoblasts. FACS analysis revealed that PDL cells, including cell populations, expressed the stem cell markers CD105, CD166, and STRO-1. CONCLUSION: The findings of this study indicated that PDL cells possess crucial stem cell properties, such as self-renewal and multipotency, and express the mesenchymal stem cell markers CD105, CD166, and STRO-1 on their cell surface, although there were some variations. Thus, PDL cells can be used for periodontal regenerative procedures.

Adipogenesis↗

PubMed1994

Stem cells and transcription factors in the development of the mammalian neural crest.

The neural crest is a migratory population of multipotent embryonic cells that generates the neurons and glia of the peripheral nervous system, as well as a variety of non-neural mesectodermal and endocrine cell types. The study of neural crest cell and molecular biology provides a system to investigate how such multipotent cells choose their fates, and whether the repertoire of fates becomes progressively restricted with time. The study of mammalian neural crest development has lagged behind studies of avian crest development due to the relative inaccessibility of mammalian embryos. The development of reverse genetic methods in mice, however, has made the analysis of mammalian neural crest development both more attractive and more tractable. Rodent neural crest cells have been isolated and grown in clonogenic cultures, where they behave as multipotent stem cells. This system provides an assay for factors that influence the differentiation of these multipotent cells. Transcription factors provide valuable early markers for neural crest cells as well as molecular handles on the lineage segregation process. One such factor is Mash1, a homolog of the Drosophila proneural genes, achaete-scute. Mash1 marks autonomic progenitor cells and is essential for their development in vivo, as shown by gene knockout experiments.

Animals↗

PubMed2006

[Stem cells from human adipose tissue: a new tool for pharmacological studies and for clinical applications].

Multipotent adult stem cells constitute an unlimited source of differentiated cells that could be used in pharmacological studies and in medicine. The presence of stem cells in different tissues, such as bone marrow, skin, muscle, has been reported. However, stem cells are rare in these tissues, are difficult to isolate and to maintain ex vivo. As adipose tissue allows extraction of a large volume of tissue with limited morbidity, this tissue could be an exciting alternative stem cell source. We have recently identified and isolated multipotent stem cells from adipose tissue of young donors. These cells, named human Multipotent Adipose-Derived Stem (hMADS) cells, exhibit features of stem cells, i.e. a high ability to self-renew and the capacity to differentiate in different lineages at the single cell level. The adipocyte differentiation of hMADS cells has been thoroughly studied and differentiated cells exhibit the unique characteristics of human adipocytes. The effects of HIV drugs on the development of hMADS cells into adipocytes will be discussed. Finally, the therapeutic potential of hMADS cells has been revealed after their transplantation into muscles of mdx mice, an animal model of Duchenne muscular dystrophy. Therefore, hMADS cells provides a powerful cellular model for drug screenings and their regenerative properties suggest that these cells could be an important tool for cell-mediated therapy.

Adiponectin↗

PubMed1998

Stimulation of activin receptor II signaling pathways inhibits differentiation of multiple gastric epithelial lineages.

Activins are TGFbeta family members known to mediate a variety of developmental events. We examined the effects of activins on the self-renewing epithelial lineages present in gastric units of the adult mouse stomach. These lineages are descended from multipotent stem cells located in the midportion of each unit. The stem cell and its immediate descendants can be identified by their morphological features. Studies of knockout mice lacking activins A or B, and/or activin type II receptors (ActRII) revealed that ActRII-mediated signaling is not required for normal gastric epithelial morphogenesis or homeostasis. Mice homozygous for a null allele of the alpha-inhibin gene (inha[m1/m1]) develop gonadal sex cord stromal tumors that secrete large amounts of activins A and B. Analysis of inha(m1/m1) mice, with or without gonads, established that supraphysiological levels of activins block differentiation of preparietal to acid-producing parietal cells, differentiation of neck cells to pepsinogen-producing zymogenic cells, and terminal differentiation of mucus-producing pit cells. ActRII mRNA is normally present in pit, parietal, and zymogenic cells. inha(m1/m1)actRII(m1/m1) compound homozygotes develop activin-secreting gonadal tumors but have no abnormalities in their gastric epithelium, indicating that persistent stimulation of ActRII-dependent signaling pathways produces pleiotrophic effects on gastric epithelial differentiation. When a lineage-specific promoter is used to ablate mature parietal cells with an attenuated diphtheria toxin A fragment in transgenic mice, there is increased proliferation of the multipotent gastric stem cell and its committed daughters and subsequent development of gastric neoplasia. Parietal cell loss in inha(m1/m1) mice is not associated with this proliferative response. These different responses to parietal cell loss suggest that stimulation of ActRII-dependent signaling pathways in inha(m1/m1) animals affects the proliferative activity of the stem cell and its immediate descendents. This finding may have therapeutic significance.

Activin Receptors↗