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PubMed2006

Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology.

For more than a decade the 'neurosphere assay' has been used to define and measure neural stem cell (NSC) behavior, with similar assays now used in other organ systems and in cancer. We asked whether neurospheres are clonal structures whose diameter, number and composition accurately reflect the proliferation, self-renewal and multipotency of a single founding NSC. Using time-lapse video microscopy, coculture experiments with genetically labeled cells, and analysis of the volume of spheres, we observed that neurospheres are highly motile structures prone to fuse even under ostensibly 'clonal' culture conditions. Chimeric neurospheres were prevalent independent of ages, species and neural structures. Thus, the intrinsic dynamic of neurospheres, as conventionally assayed, introduces confounders. More accurate conditions (for example, plating a single cell per miniwell) will be crucial for assessing clonality, number and fate of stem cells. These cautions probably have implications for the use of 'cytospheres' as an assay in other organ systems and with other cell types, both normal and neoplastic.

Animals↗
PubMed1993

Expression of human colony-stimulating factor-1 (CSF-1) receptor in murine pluripotent hematopoietic NFS-60 cells induces long-term proliferation in response to CSF-1 without loss of erythroid differentiation potential.

NFS-60 and FDCP-Mix cells are interleukin-3--dependent multipotent hematopoietic cells that can differentiate in vitro into mature myeloid and erythroid cells. Retrovirus-mediated transfer of the human colony-stimulating factor-1 (CSF-1) receptor gene (c-fms) enabled NFS-60 cells but not FDCP-Mix cells to proliferate in response to CSF-1. The phenotype of NFS-60 cells expressing the human CSF-1 receptor (CSF-1R) grown in CSF-1 did not grossly differ from that of original NFS-60 as assessed by cytochemical and surface markers. Importantly, these cells retained their erythroid potentiality. In contrast, a CSF-1-dependent variant of NFS-60, strongly expressing murine CSF-1R, differentiated into monocyte/macrophages upon CSF-1 stimulation and almost totally lost its erythroid potentiality. We also observed that NFS-60 but not FDCP-Mix cells could grow in response to stem cell factor, (SCF), although both cell lines express relatively high amounts of SCF receptors. This suggests that SCF-R and CSF-1R signalling pathways share at least one component that may be missing or insufficiently expressed in FDCP-Mix cells. Taken together, these results suggest that human CSF-1R can use the SCF-R signalling pathway in murine multipotent cells and thereby favor self-renewal versus differentiation.

Animals↗
PubMed1989

Cell lineage analysis reveals multipotent precursors in the ciliary margin of the frog retina.

The eyes of lower vertebrates grow throughout life by the proliferation of cells in the ciliary margin. To determine the range of cell types that descend from single cells of the ciliary margin in Xenopus laevis embryos, a cell lineage study was performed. Precursor cells in the periphery of the eyes were labeled by intracellular injection of rhodamine dextran, and the proliferation of these cells resulted in clones of labeled descendants. The number of cells per clone was quite variable (range, 1 to 104 cells). This broad range of sizes (compared to clones derived from optic vesicle cells) and their distribution suggest that there may be two types of ciliary margin cells with different proliferative fates: self-renewing stem cells and cells that undergo a limited number of divisions. Labeled descendants in the neural retina differentiated into all of the major cell types, including glia. One-quarter of the clones had labeled descendants in both the neural retina and the pigmented epithelium. These observations suggest that ciliary margin cells are multipotent for all neural, glial, and pigmented epithelial cell types of the eye. Thus, the molecular events that regulate the commitment of specific cell types must occur late in the cell lineages of the ciliary margin.

Animals↗
PubMed1999

"Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain.

Many diseases of the central nervous system (CNS), particularly those of genetic, metabolic, or infectious/inflammatory etiology, are characterized by "global" neural degeneration or dysfunction. Therapy might require widespread neural cell replacement, a challenge not regarded conventionally as amenable to neural transplantation. Mouse mutants characterized by CNS-wide white matter disease provide ideal models for testing the hypothesis that neural stem cell transplantation might compensate for defective neural cell types in neuropathologies requiring cell replacement throughout the brain. The oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally" dysfunctional because they lack myelin basic protein (MBP) essential for effective myelination. Therapy, therefore, requires widespread replacement with MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth-using a simple intracerebroventricular implantation technique-resulted in widespread engraftment throughout the shi brain with repletion of MBP. Accordingly, of the many donor cells that differentiated into oligodendroglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean = approximately 40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore, "global" neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.

Animals↗
PubMed2006

Reactive astrogliosis induces astrocytic differentiation of adult neural stem/progenitor cells in vitro.

Neural stem cells reside in defined areas of the adult mammalian brain, including the dentate gyrus of the hippocampus. Rat neural stem/progenitor cells (NSPCs) isolated from this region retain their multipotency in vitro and in vivo after grafting into the adult brain. Recent studies have shown that endogenous or grafted NSPCs are activated after an injury and migrate toward lesioned areas. In these areas, reactive astrocytes are present and secrete numerous molecules and growth factors; however, it is not currently known whether reactive astrocytes can influence the lineage selection of NSPCs. We investigated whether reactive astrocytes could affect the differentiation, proliferation, and survival of adult NSPCs by modelling astrogliosis in vitro, using mechanical lesion of primary astrocytes. Initially, it was found that conditioned medium from lesioned astrocytes induced astrocytic differentiation of NSPCs without affecting neuronal or oligodendrocytic differentiation. In addition, NSPCs in coculture with lesioned astrocytes also displayed increased astrocytic differentiation and some of these NSPC-derived astrocytes participated in glial scar formation in vitro. When proliferation and survival of NSPCs were analyzed, no differential effects were observed between lesioned and nonlesioned astrocytes. To investigate the molecular mechanisms of the astrocyte-inducing activity, the expression of two potent inducers of astroglial differentiation, ciliary neurotrophic factor and leukemia inhibitory factor, was analyzed by Western blot and shown to be up-regulated in conditioned medium from lesioned astrocytes. These results demonstrate that lesioned astrocytes can induce astroglial differentiation of NSPCs and provide a mechanism for astroglial differentiation of these cells following brain injury.

Analysis of Variance↗
PubMed2000

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways.

The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to fix the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary differentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are reflected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

Animals↗
PubMed1997

[Morphological and cytochemitry features of CD34+ hematopoietic cells isolated from human bone marrow].

OBJECTIVE: To explore the cytomorphological and cytochemitry features of CD34+ hematopoietic cells. METHODS: Highly purified CD34+ hematopoietic cells isolated from human bone marrow by a two-step method of immunomagnetic beads-FACS sorting were comprehensively examined. RESULTS AND CONCLUSION: CD34+ hematopoietic cells could be sorted into three types in light of morphology and cytochemical staining. Type I was considered as candidates for stem cells,which were most blastlike in morphology and slightly larger than lymphocytes in size with negative reactions to all cytochemical stainings. Type II was considered as multipotent progenitor cells, with sizes similar to small lymphocytes and negative reactions to all cytochemical stainings. Type III was identified as committed progenitor cells whose sizes were heterogeneous and whose reactions to cytochemical stainings ranged from +/- to + +.

Antigens, CD34↗
PubMed2004

Neural stem cells transplanted into intact brains as neurospheres form solid grafts composed of neurons, astrocytes and oligodendrocyte precursors.

Neural stem cells (NSCs) are tissue-specific stem cells with self-renewal potential that can give rise to neurons and glia in vivo and in vitro. The aim of this study was to transplant NSCs as whole neurospheres into intact brain and assess the fate and phenotype of their progeny generated in vivo. We isolated NSCs from E14 foetal rat forebrains and cultured them in basic fibroblast and epidermal growth factor-supplemented serum-free medium in the form of neurospheres in vitro. Neurospheres were transplanted into the intact brains of 2 Wistar rats and after a period of 3 weeks, grafted brains were examined immunohistochemically. Neurospheres formed solid grafts that were found in the lateral ventricle and in the velum interpositum under the hippocampus. The majority of cells in the transplanted tissue were identified as beta-III-tubulin(+), NeuN(+), PanNF(+) and synaptophysin(+) neurons and were accumulated throughout the graft centre. GFAP(+) astrocytes were scattered throughout the entire graft and astrocyte processes delimited the outer and perivascular surfaces. A great number of NG2(+) oligodendrocyte precursors was detected. Nestin(+) endothelial cells were found to line capillaries growing in the transplant. These data indicate that nestin(+) NSCs prevailing in neurospheres differentiate following transplantation into nestin(-) neuronal and glial cells which confirms the multipotency of NSCs. Three weeks posttransplantation neuronal and astrocyte cells reached terminal differentiation (formation of synaptic vesicles and superficial and perivascular limiting membranes) while elements of oligodendroglial cell lineage remained immature. Grafting stem cells as non-dissociated neurospheres provide cells with favourable conditions which facilitate cell survival, proliferation and differentiation. However, in the intact brain, grafted neurosphere cells were not found to integrate with the brain parenchyma and formed a compact structure demarcated from its surroundings.

Animals↗
PubMed1999

Prospects for the clinical application of neural transplantation with the use of conditionally immortalized neuroepithelial stem cells.

Although neural transplantation has made a relatively successful transition from the animal laboratory to human neurosurgery for the treatment of Parkinson's disease, the use of human embryonic brain tissue as the source of transplants raises difficult ethical and practical problems. These are likely to impede the widespread use of this otherwise promising therapy across the range of types of brain damage to which the results of animal experiments suggest its potential applicability. Various alternative approaches are reviewed briefly, aimed at developing sources of tissue for transplantation that can be maintained in vitro until needed, so obviating the requirement for fresh embryonic tissue at each occasion of surgery. Particularly promising are conditionally immortalized neuroepithelial stem cell lines in which the immortalizing gene is downregulated upon transplantation into a host brain. We describe experiments from our laboratory with the use of cells of this kind, the multipotent MHP clonal cell lines, derived from the developing hippocampus of a transgenic mouse harbouring a temperature-sensitive oncogene. Implanted into the hippocampus of rats and marmosets with damage to the CA1 cell field, the MHP36 line gave rise to healthy surviving grafts and to essentially complete recovery of cognitive function. Postmortem study of the implanted rat brains indicated that MHP36 cells migrate to the region of damage, adopt both neuronal (pyramidal) and glial phenotypes in vivo, and reconstitute the normal laminated appearance of the CA1 cell field. We have previously shown that, when primary differentiated foetal tissue is used as the source of grafts in rats with CA1 damage, there is a stringent requirement for replacement with homotypic CA1 cells. We interpret our results as showing that the MHP36 cell line responds to putative signals associated with damage to the hippocampus and takes up a phenotype appropriate for the repair of this damage; they therefore open the way to the development of a novel strategy with widespread applicability to the treatment of the diseased or damaged human brain.

Animals↗
PubMed1995

Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation.

CD25 expression occurs early in thymocyte differentiation. The mechanism of induction of CD25 before T cell receptor rearrangement and the importance of this mechanism for T cell development are unknown. In a thymus reconstitution assay, tumor necrosis factor alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha), two cytokines produced within the thymic microenvironment, induced CD25 expression on early immature thymocytes. Either TNF-alpha or IL-1 alpha was necessary for further thymocyte maturation and CD4+CD8+ differentiation. In irradiated mice reconstituted with CD117+CD25+ thymocytes, commitment to the T cell lineage was marked by the loss of precursor multipotency.

Animals↗
PubMedDate not supplied

Monitoring of hematopoietic recovery after autologous stem cell transplantation by analysis of G alpha 16 mRNA and CD34 surface glycoprotein.

The hematopoiesis-specific G protein alpha subunit G alpha16 was shown to be expressed in early normal and malignant hematopoietic cell lines and has been suggested to play an important role in signal transduction of hematopoiesis. We previously demonstrated a strict correlation of G alpha16 mRNA and CD34 antigen expression in peripheral blood stem cells (PBSC). In PBSC mobilization, both markers are detectable at the time of hematopoietic recovery and progenitor cell release. In this study the possible use of G alpha16 determination in peripheral blood samples for monitoring patients undergoing stem cell transplantation was investigated. Normal peripheral blood is negative for G alpha16 expression. In all five patients G alpha16 mRNA expression appeared shortly before the time of blood cell recovery. When tested together with CD34 (three cases) a pattern different from CD34 antigen expression was found, reflecting a different mechanism of action. In two cases with different time points of leukocyte and platelet recovery G alpha16 mRNA was detected at both time points but not in the interval, thus suggesting a role of G alpha16 in multipotent precursor cells. CD34 mRNA tested in three patients was not detected at any time; this argues for different regulation of CD34 and G alpha16 mRNA. G alpha16 may be used as an indicator of hematopoietic recovery after autologous stem cell transplantation, suggesting that there are cell type-specific G protein-mediated signal transduction pathways of early hematopoiesis.

Adult↗
PubMed2005

Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental "niches" in culture: a two-stage hypothesis for regulation of MSC fate.

Mesenchymal stem cells (MSCs) are clonal, plastic adherent cells from bone marrow that can differentiate into various tissue lineages, including osteoblasts, adipocytes, chondrocytes, myoblasts, hepatocytes, and possibly even neural cells. Because MSCs are multipotent and their numbers are easily expanded in culture, there has been much interest in their clinical potential for tissue repair and gene therapy. Consequently, numerous studies have been carried out demonstrating the migration and multiorgan engraftment potential of MSCs in animal models and in human clinical trials. Understanding the mechanisms behind MSC cell fate determination is not easy, because the molecular processes that drive engraftment and differentiation are complex. Even in an in vitro system, the molecular cues necessary to induce differentiation are not easily identified or reproduced. In this Perspective, we emphasize the importance of microenvironmental factors in culture and suggest that MSC differentiation in vitro is regulated by a two-stage mechanism involving preconditioning by factors in the culture microenvironment followed by response to soluble differentiating factors.

Adult↗
PubMed2006

Identification of genes expressed in retinal progenitor/stem cell colonies isolated from the ocular ciliary body of adult mice.

Rare pigmented cells showing retinal stem cell characteristics have been identified in the ocular ciliary body (CB) of adult mammals. In vitro, these cells were reported to clonally proliferate and generate pigmented sphere colonies (PSC) containing multipotent retinal progenitor-like cells. Because these cells may have important clinical applications and because their embryonic origin is unclear, we have analyzed their local environment and gene expression profile. We found that transcription factors Pax6, Six3, and Rx, all involved in early eye morphogenesis, were expressed in the CB of adult mice. By sequencing a PSC cDNA library, we found that PSC expressed at high levels transcripts involved in the control of redox metabolism and cellular proliferation. PSC also expressed the retinal transcription factor Six6, which expression was not detected in the CB epithelium. By in situ hybridization screen, we found that Palmdelphin (Palm), Hmga2, and a novel transcript were expressed in the central nervous system of early embryos. Palm expression delineated the pigmented epithelium of the future CB and the developing myotome. Hmga2 was expressed in the ventricular zone of the telencephalon, the developing retinal ciliary margin and lens. Several genes expressed in PSC were also expressed in the nasal anlagen. Taken together, our study reveals that PSC isolated from the ocular CB express genes involved in the control of embryonic development, retinal identity, redox metabolism, and cellular proliferation.

Animals↗
PubMed1988

Proliferation and differentiation of highly enriched mouse hematopoietic stem cells and progenitor cells in response to defined growth factors.

Three distinct hematopoietic populations derived from normal bone marrow were analyzed for their response to defined growth factors. The Thy-1loT- B- G- M-population, composing 0.2% of bone marrow, is 370-fold enriched for pluripotent hematopoietic stem cells. The two other populations, the Thy-1- T- B- G- M- and the predominantly mature Thy-1+ T+ B+ G+ M+ cells, lack stem cells. Thy-1loT- B- G- M- cells respond with a frequency of one in seven cells to IL-3 in an in vitro CFU-C assay, and give rise to many mixed colonies as expected from an early multipotent or pluripotent progenitor. The Thy-1- T- B- G- M- population also contains progenitor cells which responded to IL-3. However, colonies derived from Thy-1- T- B- G- M- cells are almost exclusively restricted to the macrophage/granulocyte lineages. This indicates that IL-3 can stimulate at least two distinct clonogenic early progenitor cells in normal bone marrow: multipotent Thy-1loT- B- G- M- cells and restricted Thy-1- T- B- G- M- cells. Thy-1loT- B- G- M-cells could not be stimulated by macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF) or IL-5 (Eosinophil-CSF). The hematopoietic precursors that react to these factors are enriched in the Thy-1- T- G- B- M- population. Thus, multipotent and restricted progenitors can be separated on the basis of the expression of the cell surface antigen Thy-1.

Animals↗
PubMed2002

Fetal brain progenitor cells transdifferentiate to fates outside the nervous system.

Central nervous system stem cells give rise to neurons and glia when exposed to specific trophic factors. In our studies with rat fetal brain-derived stem cells (RSCs), we showed that they could be induced to express the developmentally regulated transcription factors and cell markers characteristic of cells derived from another germ layer, e.g. pituitary cells. Therefore, rat fetal brain-derived stem cells do not seem to be restricted to a defined developmental fate. They may retain pluripotentiality and can be redirected to develop into other cell types not found in the brain provided the correct set of stimuli is present. This multipotent developmental behavior also suggests that instructive signals are operative.

Animals↗
PubMed2007

Isolation of amniotic stem cell lines with potential for therapy.

Stem cells capable of differentiating to multiple lineages may be valuable for therapy. We report the isolation of human and rodent amniotic fluid-derived stem (AFS) cells that express embryonic and adult stem cell markers. Undifferentiated AFS cells expand extensively without feeders, double in 36 h and are not tumorigenic. Lines maintained for over 250 population doublings retained long telomeres and a normal karyotype. AFS cells are broadly multipotent. Clonal human lines verified by retroviral marking were induced to differentiate into cell types representing each embryonic germ layer, including cells of adipogenic, osteogenic, myogenic, endothelial, neuronal and hepatic lineages. Examples of differentiated cells derived from human AFS cells and displaying specialized functions include neuronal lineage cells secreting the neurotransmitter L-glutamate or expressing G-protein-gated inwardly rectifying potassium channels, hepatic lineage cells producing urea, and osteogenic lineage cells forming tissue-engineered bone.

Amniotic Fluid↗
PubMed2003

Priming the hematopoietic pump.

Markers of multiple hematopoietic lineages are expressed in multipotent progenitors, a phenomenon referred to as "lineage priming." A new study in this issue of Immunity provides compelling evidence that such "promiscuous" gene expression occurs in hematopoietic stem cells and does not interfere with their long-term repopulation potential.

Cell Differentiation↗