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PubMed2002

Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.

The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic beta cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.

Androstadienes↗
PubMed1999

Clinical utility in maximizing CD34+ cell count in stem cell grafts.

Many different stem cell subsets have been identified. Some of these subsets are multipotent, able to develop into any one of several cell types, while other stem cell subsets are committed to differentiated myeloid, lymphoid, erythroid, or megakaryocytic lineages.

Antigens, CD34↗
PubMed2004

Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4.

BACKGROUND: Spontaneous repair is limited after CNS injury or degeneration because neurogenesis and axonal regrowth rarely occur in the adult brain. As a result, cell transplantation has raised much interest as potential treatment for patients with CNS lesions. Several types of cells have been considered as candidates for such cell transplantation and replacement therapies. Foetal brain tissue has already been shown to have significant effects in patients with Parkinson's disease. Clinical use of the foetal brain tissue is, however, limited by ethical and technical problems as it requires high numbers of grafted foetal cells and immunosuppression. Alternatively, several reports suggested that mesenchymal stem cells, isolated from adult bone marrow, are multipotent cells and could be used in autograft approach for replacement therapies. RESULTS: In this study, we addressed the question of the possible influence of mesenchymal stem cells on neural stem cell fate. We have previously reported that adult rat mesenchymal stem cells are able to express nestin in defined culture conditions (in the absence of serum and after 25 cell population doublings) and we report here that nestin-positive (but not nestin-negative) mesenchymal stem cells are able to favour the astroglial lineage in neural progenitors and stem cells cultivated from embryonic striatum. The increase of the number of GFAP-positive cells is associated with a significant decrease of the number of Tuj1- and O4-positive cells. Using quantitative RT-PCR, we demonstrate that mesenchymal stem cells express LIF, CNTF, BMP2 and BMP4 mRNAs, four cytokines known to play a role in astroglial fate decision. In this model, BMP4 is responsible for the astroglial stimulation and oligodendroglial inhibition, as 1) this cytokine is present in a biologically-active form only in nestin-positive mesenchymal stem cells conditioned medium and 2) anti-BMP4 antibodies inhibit the nestin-positive mesenchymal stem cells conditioned medium inducing effect on astrogliogenesis. CONCLUSIONS: When thinking carefully about mesenchymal stem cells as candidates for cellular therapy in neurological diseases, their effects on resident neural cell fate have to be considered.

Animals↗
PubMed2006

The therapeutic potential of adult neural stem cells.

Neural stem cells (NSCs) are self-renewing, multipotent cells that generate the neuronal and glial cells of the nervous system. In mammals, contrary to long-held belief, neurogenesis occurs in the adult brain, and NSCs reside in the adult central nervous system. Thus, the brain may be amenable to repair following damage, and new avenues for cell-based therapy are being considered for the treatment of brain disease and injury, such as the stimulation of endogenous progenitor cells, the transplantation of adult-derived neural progenitor and stem cells, and, in particular, autologous cell transplantation. Although significant advances in this field have been made over the past decade, the adult NSC remains an elusive cell for study, and researchers are facing multiple challenges to the development of therapeutic applications from adult NSC research. Among these challenges are the identification and characterization of NSCs in vivo and in vitro, the understanding of the physiology of newly generated neuronal cells in the adult brain, the stimulation of endogenous progenitor cells to promote functional recovery, and the isolation and culture of homogenous populations of neural progenitor or stem cells from the adult brain for cell-based therapy.

Adult Stem Cells↗
PubMed2002

Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies.

OBJECTIVE: Mesenchymal stem cells (MSCs) are a population of multipotent cells that can proliferate and differentiate into multiple mesodermal tissues. We previously reported that monoclonal antibodies to the low-affinity nerve growth factor receptor (alpha-LNGFR) stain bone marrow (BM) mesenchymal cells. We now show that LNGFR antibodies label primitive MSCs with high specificity and purity in adult BM, and compare these cells to those isolated by plastic adherence (PA) and CD45(-)anti-glycophorin A(-) selection. MATERIALS AND METHODS: Low-density mononuclear cells (LD-MNCs) from normal BM were separated by PA or immunomagnetic selection for NGFR(+) or CD45(-)alpha-glycophorin A(-) cells. The three fractions were grown in Iscove's modified Dulbecco medium + 20% fetal bovine serum +/- basic fibroblast growth factor (bFGF) in order to assess their proliferative capacity and evaluate their phenotype during culture. The clonogenic potential of the MSCs was assessed using a colony-forming unit fibroblast (CFU-F) assay, whereas multipotential differentiation was determined after culture in adipocytic and osteoblastic conditioned media. RESULTS: The NGFR(+) mesenchymal cells grown without growth factors showed persistent NGFR expression (rapidly down-regulated after the addition of bFGF) and persistent CFU-F activity. The NGFR(+) fractions were rich in clonogenic precursors: CFU-F median frequency was 1584/1 x 10(6) cells (range 325-13,793) in the NGFR(+) cells and 35/1 x 10(6) cells (range 27-112) in the LD-MNCs. The NGFR(-) fraction never showed any residual CFU-F activity. Compared with the other two fractions, the NGFR(+) cells (+/- bFGF) showed a 1 to 3 log greater expansion in the number of fibroblastic cells and a greater capacity to give rise to adipocyte colonies and induce osteoblastic differentiation, and they had similar effects in supporting the growth of hematopoietic precursors. CONCLUSION: The data suggest that positive selection using low-affinity NGFR antibodies makes it possible to obtain homogeneous multipotent MSCs.

Adipocytes↗
PubMed2002

The first 3 days of B-cell development in the mouse embryo.

B-lineage-committed cells are believed to arise in the liver of mouse embryos at 14 days after coitus (dpc). However, pre-B-specific gene transcripts and DJH gene rearrangements have been detected in earlier, midgestation embryos. We describe here a population of c-kit(+)AA4.1(+)CD19(+)Pax5(+) cells present in the aorta-gonad-mesonephros (AGM) area and in the livers of 11-dpc mouse embryos. In contrast to multipotent c-kit(+)AA4.1(+)CD19(-) hematopoietic stem cells (HSCs), these c-kit(+)AA4.1(+)CD19(+) progenitors differentiated only to B-lineage cells in vitro. We propose that mouse embryonic B lymphopoiesis starts earlier than previously thought, at 10 to 11 dpc, both in liver and extra-liver hematopoietic sites. The B-cell differentiation program is not delayed with respect to the emerging lymphohematopoiesis events in the midgestation mouse embryo (8-9 dpc).

Animals↗
PubMed2006

Neurosphere assays: growth factors and hormone differences in tumor and nontumor studies.

The "no new neuron" dogma that the brain is quiescent throughout adult life has been challenged by the discovery of cells with stem cell-like qualities of self-renewal and multipotency in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in adults. This self-renewing capacity also makes these neural stem cells a possible source of brain tumors, which was supported by the discovery of self-sustaining brain tumor stem-like cells in cancers such as glioblastoma multiforme. Neurosphere assays are the standard for studying these stem-like cells in both normal and cancer tissues. Despite the importance of these assays, there is no standardized protocol to allow for a comparison of results because several studies use different growth factors and hormones at different concentrations. The primary objective of this study is to review the literature for both nontumor and tumor studies to assess their respective neurosphere assay components. We found significant variation in assay components, namely hormones and growth factors, as well as their respective concentrations. This illustrates the need for a standardized protocol to allow proper comparison among studies and a better assessment of the effects of different factors.

Animals↗
PubMed2003

Development of lymphoid lineages from embryonic stem cells in vitro.

Lymphocyte development proceeds through highly ordered and regulated stages, as multipotent hematopoietic progenitors differentiate into lineage-defined progenitors, and ultimately into mature effector cells. The ability to generate lymphocytes from embryonic stem (ES) cells in vitro should facilitate the study of these complex differentiation steps by providing a model system in which the effects of genetic and nongenetic manipulations can be examined in a controlled setting. These advances may also contribute to future therapeutic approaches. In this article, we describe the procedure for generating functional lymphocytes from mouse ES cells.

Animals↗
PubMed2001

Multilineage cells from human adipose tissue: implications for cell-based therapies.

Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.

Adipocytes↗
PubMed1995

Human neuroblastoma I-type cells are malignant neural crest stem cells.

Human neuroblastoma I-type cells isolated from cell lines in vitro are morphologically intermediate between neuroblastic (N) cells, with properties of embryonic sympathoblasts, and substrate-adherent (S) cells having properties of embryonic Schwann/glial/melanocytic cells of the neural crest. I cells have biochemical features of both N and S cells. We propose that the I-type cell represents a malignant neural crest stem cell. The strongest evidence in support of this hypothesis is that: (a) I cells can generate progeny that have neuronal properties, i.e., are committed neuroblasts, or properties of nonneuronal, embryonic neural crest-derived cells; and (b) I-type cells can generate multipotent I-type progeny, indicating their capacity for self-renewal, a feature of stem cells. We report here that I-type cells, derived from four different human neuroblastoma cell lines and experimentally induced to differentiate, give rise to cells with distinct N or S cell phenotypes, indicative of I cell multipotentiality. Experiments with a large panel of I-type subclones, isolated from clonal I-type BE(2)-C cells and exposed to retinoic acid to induce neuronal differentiation or 5-bromo-2'-deoxyuridine to obtain S-type cells, demonstrated that differentiation occurs via induction and selection and not by selection of spontaneously arising variants. The differentiation phenotype was stable. We conclude that human neuroblastoma I-type cells are multipotent embryonic precursor cells of the peripheral nervous system, capable of either neuronal or nonneuronal neural crest cell differentiation.

Bromodeoxyuridine↗
PubMed2004

Differentiation of B lymphocytes from hematopoietic stem cells.

Differentiation of B lymphocytes can be efficiently obtained when multipotent hematopoietic precursors are cocultured with stromal cell lines and soluble growth factors. Stromal cell lines provide yet-undefined signals required for the expansion of the precursor population and/or lineage commitment and soluble mediators. In consequence, the type of the exogenously added interleukins depends on the stromal support used in the assay. In contrast to S17 and OP9 stroma, the fibroblast line NIH3T3 does not support B-cell precursor expansion of CD19(+) fetal liver cells; neither does it induce B-lineage differentiation from embryonic multipotent progenitors, in the absence of added cytokines. Under these conditions c-kit ligand, interleukin-7 (IL-7), and Flt3 ligand (Flt3-L) are added to the cultures to ensure optimal B-cell differentiation. Another cytokine, stroma-derived lymphopoietin, can also be used instead of IL-7 in embryonic but not adult hematopoietic precursors.

Animals↗
PubMed2004

Human neural stem cells normalize rat behavior after hypoxia.

Transplants of cultured neural stem cells from human brain survived, retained multipotent activity, and produced a neuroprotective effect on degenerating neurons in the brain of adult rats subjected to hypoxic hypoxia. They normalized animal behavior and improved conditioning in two-way avoidance response paradigm in a shuttle box.

Animals↗
PubMed2005

In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells.

In addition to long-term self-renewal capability, human mesenchymal stem cells (MSCs) possess versatile differentiation potential ranging from mesenchyme-related multipotency to neuroectodermal and endodermal competency. Of particular concern is hepatogenic potential that can be used for liver-directed stem cell therapy and transplantation. In this study, we have investigated whether human umbilical cord blood (UCB)-derived MSCs are also able to differentiate into hepatocyte-like cells. MSCs isolated from UCB were cultured under the pro-hepatogenic condition similar to that for bone marrow (BM)-derived MSCs. Expression of a variety of hepatic lineage markers was analyzed by flow cytometry, RT-PCR, Western blot, and immunofluorescence. The functionality of differentiated cells was assessed by their ability to incorporate DiI-acetylated low-density lipoprotein (DiI-Ac-LDL). As the cells were morphologically transformed into hepatocyte-like cells, they expressed Thy-1, c-Kit, and Flt-3 at the cell surface, as well as albumin, alpha-fetoprotein, and cytokeratin-18 and 19 in the interior. Moreover, about a half of the cells were found to acquire the capability to transport DiI-Ac-LDL. Based on these observations, and taking into account immense advantages of UCB over other stem cell sources, we conclude that UCB-derived MSCs retain hepatogenic potential suitable for cell therapy and transplantation against intractable liver diseases.

Acetylation↗
PubMed2000

Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS.

The ready availability of unlimited quantities of neural stem cells derived from the human brain holds great interest for basic and applied neuroscience, including therapeutic cell replacement and gene transfer following transplantation. We report here the combination of epigenetic and genetic procedures for perpetuating human neural stem cell lines. Thus we tested various culture conditions and genes for those that optimally allow for the continuous, rapid expansion and passaging of human neural stem cells. Among them, v-myc (the p110 gag-myc fusion protein derived from the avian retroviral genome) seems to be the most effective gene; we have also identified a strict requirement for the presence of mitogens (FGF-2 and EGF) in the growth medium, in effect constituting a conditional perpetuality or immortalization. A monoclonal, nestin-positive, human neural stem cell line (HNSC.100) perpetuated in this way divides every 40 h and stops dividing upon mitogen removal, undergoing spontaneous morphological differentiation and upregulating markers of the three fundamental lineages in the CNS (neurons, astrocytes, and oligodendrocytes). HNSC.100 cells therefore retain basic features of epigenetically expanded human neural stem cells. Clonal analysis confirmed the stability, multipotency, and self-renewability of the cell line. Finally, HNSC.100 can be transfected and transduced using a variety of procedures and genes encoding proteins for marking purposes and of therapeutic interest (e.g., human tyrosine hydroxylase I).

Blotting, Southern↗
PubMed2004

Neural stem and progenitor cells: choosing the right Shc.

Neural stem cell (NSCs) are self-renewing, multipotent cells able to generate neurons, astrocytes and oligodendrocytes. Since their identification, these properties have made NSCs an attractive subject for therapeutic applications to the damaged brain. In this context, understanding the mechanisms and the molecules regulating their biological properties is important and it is focused to gain control over their proliferative and differentiative potential. Here we will discuss values and unsolved aspects of the system and the employment of potentially key molecular targets for proper control of NSCs fate.

Adaptor Proteins, Signal Transducing↗
PubMed2005

The adult Drosophila posterior midgut is maintained by pluripotent stem cells.

Vertebrate and invertebrate digestive systems show extensive similarities in their development, cellular makeup and genetic control. The Drosophila midgut is typical: enterocytes make up the majority of the intestinal epithelial monolayer, but are interspersed with hormone-producing enteroendocrine cells. Human (and mouse) intestinal cells are continuously replenished by stem cells, the misregulation of which may underlie some common digestive diseases and cancer. In contrast, stem cells have not been described in the intestines of flies, and Drosophila intestinal cells have been thought to be relatively stable. Here we use lineage labelling to show that adult Drosophila posterior midgut cells are continuously replenished by a distinctive population of intestinal stem cells (ISCs). As in vertebrates, ISCs are multipotent, and Notch signalling is required to produce an appropriate fraction of enteroendocrine cells. Notch is also required for the differentiation of ISC daughter cells, a role that has not been addressed in vertebrates. Unlike previously characterized stem cells, which reside in niches containing a specific partner stromal cell, ISCs adjoin only the basement membrane, differentiated enterocytes and their most recent daughters. The identification of Drosophila intestinal stem cells with striking similarities to their vertebrate counterparts will facilitate the genetic analysis of normal and abnormal intestinal function.

Aging↗
PubMed1998

Expression of the LIM-homeobox gene LH2 generates immortalized steel factor-dependent multipotent hematopoietic precursors.

The genes controlling self-renewal and differentiation in the hematopoietic system are largely unknown. The LIM-homeobox genes are known to be important for asymmetric cell divisions and differentiation of specific cell types and organs. One member of this family, LH2, is expressed in fetal liver at the time of active hematopoiesis. Therefore, we have assessed the function of LH2 during the formation and initial expansion of the hematopoietic system by differentiating LH2-transduced embryonic stem (ES) cells in vitro. This procedure generated multipotent hematopoietic precursor cell (HPC) lines that required Steel factor for growth. HPC lines have been maintained in an undifferentiated state in culture for >7 months. Other growth factors tested efficiently induce terminal differentiation of HPCs into various mature myeloid lineages. Steel factor is also required and acts synergistically with the other growth factors to generate multilineage colonies from the HPCs. These HPC lines express transcription factors that are consistent with an immature progenitor, and the pattern of cell surface marker expression is similar to that of early fetal multipotent hematopoietic progenitors. Collectively, these data suggest that the HPC lines represent an early fetal multipotent hematopoietic progenitor, and suggest a role for LH2 in the control of cell fate decision and/or proliferation in the hematopoietic system.

Animals↗
PubMed2006

Isolation of rat bone marrow stem cells.

Stem cell research has become an important field of study for molecular, cellular, and clinical biology as well as pharmaco-toxicology. Indeed, stem cells have a strong proliferative and unlimited self-renewal potential and are multipotent. In vivo as well as in vitro studies have confirmed the differentiation of adult bone marrow stem cells into muscle cells, adipocytes, cardiomyocytes, neuroectodermal cells, osteoblasts, chondroblasts, and so on. Recently, it has been shown that, under appropriate culture conditions, adult bone marrow stem cells may also differentiate into hepatocyte-like cells. Because of their extensive proliferative capacity and pluripotency, adult bone marrow stem cells could serve in the future as an unlimited source of hepatocytes for pharmaco-toxicological research and testing. We describe a protocol for isolation of mononuclear cells from adult rat bone marrow.

Animals↗