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PubMedDate not supplied

Stem cells: you can't tell a cell by its cover.

Embryonic stem (ES) cells are capable of unlimited self-renewal and have the ability to give rise to all tissue types in the body. The use of human ES cells for tissue and cell therapeutics has been suggested, but is limited by ethical concerns as these cells are derived from the inner cell mass of human embryos. In addition, the need for HLA matching of ES cell-derived tissues for allogeneic transplantation would require a bank of several thousand ES cell lines to make tissue therapeutics practical. Recently, adult stem cells-of which those in bone marrow are the best studied-have been shown to be capable of multilineage differentiation into cells of various non-blood tissues. Umbilical cord blood (UCB) haematopoietic stem cells have been shown to be equivalent to bone marrow stem cells for reconstitution of the haematopoietic system. Preliminary studies have also demonstrated that UCB haematopoietic stem cells are multipotent and capable of differentiating into non-blood cell types. This observation raises the exciting possibility of replacing human ES cells for tissue and cell therapeutics with UCB blood haematopoietic stem cells that are normally discarded with the placenta after delivery.

Adult↗
PubMed2005

Deletion of the selection cassette, but not cis-acting elements, in targeted Flk1-lacZ allele reveals Flk1 expression in multipotent mesodermal progenitors.

Flk1, the gene encoding the vascular endothelial growth factor receptor 2 (VEGFR-2), is a well-known marker for vascular and hematopoietic progenitors and is indispensable for normal hematopoiesis and vasculogenesis. Here we show that Flk1 expression in the early mouse embryo marks a broad spectrum of mesodermal progenitors exiting the primitive streak as well as later mesodermal cell types including some cardiomyocytes, portions of the somites, and all extraembryonic mesoderm cells. These findings made use of an Flk1-lacZ knock-in allele in which the neomycin selection cassette was removed, which resulted in full replication of the endogenous expression of Flk1. Targeted deletion of a region in intron 1 that has been proposed to direct endothelial expression produced no alteration in either endothelial or broader mesodermal expression of the Flk1-lacZ allele. Examination of lacZ expression in homozygotes for the Flk1lacZ neo-out allele revealed that lacZ-expressing mesodermal cells persisted in nonvascular regions. Thus, Flk1 expression marks progenitors with broad mesodermal potential but is not absolutely required for the development of all mesodermal lineages in which it is expressed.

Alleles↗
PubMed2005

Characterization and multipotentiality of human fetal femur-derived cells: implications for skeletal tissue regeneration.

To date, the plasticity, multipotentiality, and characteristics of progenitor cells from fetal skeletal tissue remain poorly defined. This study has examined cell populations from human fetal femurs in comparison with adult-derived mesenchymal cell populations. Real-time quantitative polymerase chain reaction demonstrated expression of mesenchymal progenitor cell markers by fetal-derived cells in comparison with unselected adult-derived and immunoselected STRO-1-enriched adult populations. Multipotentiality was examined using cells derived from femurs and single-cell clones, culture-expanded from explants, and maintained in basal medium prior to exposure to adipogenic, osteogenic, and chondrogenic conditions. Adipocyte formation was confirmed by Oil Red O lipid staining and aP2 immunocytochemistry, with expression of peroxisome proliferation-activated receptor-gamma detected only in adipogenic conditions. In chondrogenic pellets, chondrocytes lodged within lacunae and embedded within dense proteoglycan matrix were observed using Alcian blue/Sirius red staining and type II collagen immunocytochemistry. Osteogenic differentiation was confirmed by alkaline phosphatase staining and type I collagen immunocytochemistry as well as by gene expression of osteopontin and osteocalcin. Single-cell clonal analysis was used to demonstrate multipotentiality of the fetal-derived populations with the formation of adipogenic, chondrogenic, and osteogenic populations. Mineralization and osteoid formation were observed after culture on biomimetic scaffolds with extensive matrix accumulation both in vitro and in vivo after subcutaneous implantation in severely compromised immunodeficient mice. These studies demonstrate the proliferative and multipotential properties of fetal femur-derived cells in comparison with adult-derived cells. Selective differentiation and immunophenotyping will determine the potential of these fetal cells as a unique alternative model and cell source in the restoration of damaged tissue.

Adipogenesis↗
PubMed2005

Liver-specific gene expression in mesenchymal stem cells is induced by liver cells.

AIM: The origin of putative liver cells from distinct bone marrow stem cells, e.g. hematopoietic stem cells or multipotent adult progenitor cells was found in recent in vitro studies. Cell culture experiments revealed a key role of growth factors for the induction of liver-specific genes in stem cell cultures. We investigated the potential of rat mesenchymal stem cells (MSC) from bone marrow to differentiate into hepatocytic cells in vitro. Furthermore, we assessed the influence of cocultured liver cells on induction of liver-specific gene expression. METHODS: Mesenchymal stem cells were marked with green fluorescent protein (GFP) by retroviral gene transduction. Clonal marked MSC were either cultured under liver stimulating conditions using fibronectin-coated culture dishes and medium supplemented with SCF, HGF, EGF, and FGF-4 alone, or in presence of freshly isolated rat liver cells. Cells in cocultures were harvested and GFP+ or GFP- cells were separated using fluorescence activated cell sorting. RT-PCR analysis for the stem cell marker Thy1 and the hepatocytic markers CK-18, albumin, CK-19, and AFP was performed in the different cell populations. RESULTS: Under the specified culture conditions, rat MSC cocultured with liver cells expressed albumin-, CK-18, CK-19, and AFP-RNA over 3 weeks, whereas MSC cultured alone did not show liver specific gene expression. CONCLUSION: The results indicate that (1) rat MSC from bone marrow can differentiate towards hepatocytic lineage in vitro, and (2) that the microenvironment plays a decisive role for the induction of hepatic differentiation of rMSC.

Animals↗
PubMed2003

Neuronal and glial differentiation following culture of the human embryonic cortical stem cells.

OBJECTIVE: To set up long-term in vitro culture system of the human neural stem cells (hNSC) and to study their biological properties. METHODS: Human fetuses aged about 20 weeks following spontaneous abortion were adopted. A serum-free medium containing basic fibroblast growth factor and epidermal growth factor was used to make the hNSCs divide continuously in the culture. The growth curve of continually passaged cells was examined. The effects of long-term culture on the cell cycle, cell differentiation were analyzed. The cell cycles of these cells were analyzed using flow cytometry. RESULTS: The cells from the human embryonic cortical tissue could be maintained and propagated in the presence of growth factors. Neurospheres were generated continually. Only one month after the primary culture, the precursors could be effectively discarded. The cells could be cultured for ten months. The cells had an exponential, consistent growth. The cell cycle analysis indicated that the hNSCs maintained remarkable proliferation. Upon differentiation, the hNSCs gave rise to mature cells. The multi-lineage potential of differentiation after different passages remained unchanged. CONCLUSION: The hNSCs isolated from the human embryonic tissues retained their biological features after long-term culture in vitro.

Cell Differentiation↗
PubMedDate not supplied

Decision making in interstitial stem cells of Hydra.

Interstitial stem cells in Hydra are a continuously proliferating and differentiating cell population. They represent a useful model system for studying mechanisms controlling stem cell differentiation. Here we review our current knowledge of the differentiation potential of these cells. Interstitial stem cells are multipotent and able to differentiate into several different cell types. The differentiation decisions appear to be controlled by positional signals and by the composition of the cellular environment. Since interstitial stem cells can be cultured in an in vivo environment and appear to be accessible to experimental manipulation by a range of new molecular techniques, an in vivo analysis of the molecular mechanisms underlying stem cell decision making can now be approached.

Amino Acid Sequence↗
PubMed2005

The transdifferentiation potential of limbal fibroblast-like cells.

We report the identification and isolation of limbal fibroblast-like cells from adult corneo-limbal tissue possessing self-renewing capacity and multilineage differentiation potential. The cells form cell aggregates or clusters, which express molecular markers, specific for ectoderm, mesoderm and endoderm lineages in vitro. Further, these cells mature into a myriad of cell types including neurons, corneal cells, osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes and pancreatic islet cells. Despite originating from a non-embryonic source, they express ESC and other stem cell markers important for maintaining an undifferentiated state. This multipotential capability, relatively easy isolation and high rate of ex vivo proliferation capacity make these cells a promising therapeutic tool.

Agar↗
PubMed2005

Silencing p21(Waf1/Cip1/Sdi1) expression increases gene transduction efficiency in primitive human hematopoietic cells.

Adult hematopoietic and other tissue stem cells have highly constrained cell cycling that limits their susceptibility to standard gene therapy vectors, which depend upon chromosomal integration. Using cytokine cocktails to increase transduction efficiency often compromises subsequent stem cell function in vivo. We previously showed that p21(Waf1/Cip1/Sdi1) (p21) mediates stem cell quiescence in vivo and decreasing its expression ex vivo leads to an expansion of stem cell pool in vivo. Here, we report that application of p21 specific siRNA increased the gene transduction efficiency in hematopoietic stem cells while preserving cell multipotentiality. Both types of siRNA, synthesized siRNA and transcribed shRNA, reduced p21 expression in target cells by 85-98%. The effect of RNAi in these cells was transient and the level of p21 mRNA returned to base line 14-28 days after siRNA treatment. This brief interval of reduction, however, was sufficient to increase transduction efficiency to two- to four-fold in cell cultures, and followed by a seven- to eight-fold increase in mice. The RNAi treated, lentivector-transduced CD34+ cells retained multipotentiality as assessed in vitro by colony formation assay and in vivo by NOD/SCID mouse transplantation assay. Reduction of p21 resulted in an increased chromosomal integration of lentivector into target cellular DNA. Taken together, both synthesized and transcribed siRNA knocked down p21 expression in human CD34+ hematopoietic stem/progenitor cells. Silencing p21 expression increased gene transduction efficiency and vector integration while retaining stem cell multipotentiality. Thus, RNAi targeting of p21 is a useful strategy to increase stem cell gene transfer efficiency. Decreasing p21 expression transiently while increasing gene-transfer vector integration may ultimately facilitate clinical applications of gene therapy.

Adult↗
PubMed2006

HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.

The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1alpha with HIF-2alpha results in expanded expression of HIF-2alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency. We show that HIF-2alpha, but not HIF-1alpha, binds to the Oct-4 promoter and induces Oct-4 expression and transcriptional activity, thereby contributing to impaired development in homozygous Hif-2alpha KI/KI embryos, defective hematopoietic stem cell differentiation in embryoid bodies, and large embryonic stem cell (ES)-derived tumors characterized by altered cellular differentiation. Furthermore, loss of HIF-2alpha severely reduces the number of embryonic primordial germ cells, which require Oct-4 expression for survival and/or maintenance. These results identify Oct-4 as a HIF-2alpha-specific target gene and indicate that HIF-2alpha can regulate stem cell function and/or differentiation through activation of Oct-4, which in turn contributes to HIF-2alpha's tumor promoting activity.

Alleles↗
PubMed2001

Progenipoietin-1: a multifunctional agonist of the granulocyte colony-stimulating factor receptor and fetal liver tyrosine kinase-3 is a potent mobilizer of hematopoietic stem cells.

OBJECTIVE: Progenipoietin-1 is an agonist of both the granulocyte colony-stimulating factor and fetal liver tyrosine kinase-3 receptors capable of inducing the proliferation of multiple hematopoietic cell lineages. The potential of progenipoietin-1 to mobilize transplantable hematopoietic stem cells into the peripheral blood was evaluated. METHODS: Cohorts of donor mice were treated with either progenipoietin-1, fetal liver tyrosine kinase-3 ligand, granulocyte colony-stimulating factor, or a vehicle control. Hematopoietic progenitor/stem-cell activity in donor blood was assayed by radioprotection, multilineage reconstitution, secondary transplantation, and competitive repopulation. RESULTS: Only 1 microL of peripheral blood from progenipoietin-1-treated donors was required to protect 80% of lethally irradiated mice, while in contrast 1 microL of peripheral blood from granulocyte colony-stimulating factor-treated donors failed to protect any recipients. The radioprotected recipients of progenipoietin-1-treated donor cells showed donor-derived (Ly5.2) multilineage hematopoietic reconstitution for up to 6 months. Serial transplantation studies using bone marrow from radioprotected, chimeric recipients demonstrated long-term donor-derived hematopoiesis, indicating the successful transplantation of multipotent hematopoietic stem cells. The engraftment potential of progenipoietin-1 donor-derived cells was directly compared with donors treated with granulocyte colony-stimulating factor or fetal liver tyrosine kinase-3 ligand alone or in combination. Both spleen colony-forming activity and competitive repopulating activity was highest in the blood from progenipoietin-1-treated donors. CONCLUSIONS: These studies demonstrate that progenipoietin-1 is a potent mobilizer of transplantable hematopoietic stem cells and indicate that this dual-receptor agonist has greater biologic activity than its constituent molecules.

Animals↗
PubMed2002

Studies on clonogenic hemopoietic cells of vertebrate in space: problems and perspectives.

Hemopoietic tissues were studied in vertebrates launched aboard the Soviet (Russian) biosatellites ("Cosmos-1129, 1514, 1667, 1887 and 2044"; "Bion-10 and 11") between 1980 and 1996. In the bone marrow of rats exposed to spaceflight conditions, a statistically significant decrease in cell number was revealed in the progenitor cell compartment accounting for the compensatory response of granulocyte-macrophage (CFU-gm) and erythrocyte lineages (BFU-e and CFU-e) and in the compartment of multipotent hemopoietic stem cells (CFU-s), which is responsible for the permanent renewal of hemopoietic tissue. The number of stromal fibroblastic progenitors (CFC-f) in the bone marrow of these rats was also reduced. Apparently, changes in the hemopoietic stroma damage the hemopoietic microenvironment and, hence, may be responsible for changes observed in the hemopoietic tissue proper. Attempts were made to develop methods for analyzing morphologically indiscernible clonogenic hemopoietic cells of newts, and studies on the effects of spaceflight factors on these cells were performed. The results showed that the numbers of clonogenic cells in newts of the flight group newts were significantly lower than in control newts. The data obtained are used as the basis for formulating the problems to be studied, drawing up a program for further research on the effects of spaceflight factors on stem and other clonogenic hemopoietic cells, and developing new experimental models for analyzing stem cells, the state of the hemopoietic stroma, etc.

Animals↗
PubMed2006

Neurogenesis in the adult rat piriform cortex.

Multipotent neural precursors have been suggested to exist in many parts of the adult mammalian brain. In the present study, we characterized the neurogenic potential in the piriform cortex of adult rats. Proliferation rates as detected by 5'-bromodeoxyuridine-labeling proved to be low when compared with the major neurogenic brain regions (i.e. the hippocampus and the subventricular zone). 5'-Bromodeoxyuridine/NeuN-labeling in accordance with doublecortin, polysialylated neural cell adhesion molecule, and TUC-4-labeling indicated that neuronal differentiation of newborn cells occurs predominantly in layer II of the piriform cortex. Many of the cells exhibited a pyramidal cell morphology. The lack of 5'-bromodeoxyuridine/NeuN-labeled cells 12 weeks after 5'-bromodeoxyuridine administration argued against long-term survival of newborn neurons in the piriform cortex.

Animals↗
PubMed2000

Stem cell characteristics of transplanted rat mammary clonogens.

Rat mammary glands contain a subpopulation of clonogenic epithelial cells with large proliferation and differentiation potentials. When transplanted, the clonogens in monodispersed rat mammary epithelial cell suspensions give rise to either alveolar units (AUs) or ductal units (DUs) depending on the nature of the hormonal milieu in the graft recipient. Clonogens are also the primary cells of origin of mammary cancer following exposure to ionizing radiation or chemical carcinogens. Given the other stem cell characteristics of mammary clonogens, it would be expected that the primary AUs and DUs to which they give rise when grafted and hormonally stimulated (a) would be derived from the same clonogenic cell subpopulation, (b) would contain all of the functionally differentiated cell types of homologous parts of comparably stimulated mammary glands in situ, and (c) would also contain clonogen subpopulations capable when subtransplanted of giving rise to secondary AUs and DUs of similar cell composition. The current experiments were designed to test these expectations. The data are discussed in the context of results of previous studies with this and other experimental models. The results further support the conclusion that rat mammary clonogens are multipotent mammary stem cells.

Animals↗
PubMed2005

Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice.

The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus. We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells. We show that Arf is a general target of Bmi1, however particularly in neural stem cells, derepression of Ink4a contributes to Bmi1(-/-) phenotypes. Additionally, we demonstrate haploinsufficient effects for the Ink4a/Arf locus downstream of Bmi1 in vivo. This suggests differential, cell type-specific roles for Ink4a versus Arf in PcG-mediated (stem) cell cycle control.

Animals↗
PubMed2002

[Stem cells from cord blood: current status and future potential].

Umbilical cord blood is rich in hematopoietic stem cells. At birth, it can be collected, HLA-typed and stored. Cord blood is successfully used since over 10 years as source of transplantation of hematopoietic stem cells, in addition to bone marrow and mobilized peripheral blood stem cells. Allogeneic transplantations are performed between HLA-identical siblings and from HLA-matched unrelated donors. Most recipients of cord blood are children with Leukemia or genetic disorders, but also increasingly adolescents and adults. Based on the promising results, cord blood banks with kryopreserved, HLA-typed cord blood samples from anonymous donors are set up worldwide, ready to be used as allogeneic stem cell graft. In addition, so-called "private" cord blood banks have been set up, providing the possibility to store cord blood at birth from healthy children with no affected family member for a possible autologous stem cell transplantation in the future if the child later develops a disease such as Leukemia. For several reasons, however, this procedure has been scientifically as well as ethically challenged. To date, there is no established indication for an autologous cord blood transplantation. Nevertheless, the plasticity and multipotency of adult stem cells, which has been recently discovered, could lead to a possible autologous use of cord blood stem cells for different indications in the field of regenerative medicine (cell- and organ replacement/regeneration). So far, however, this remains speculatative. Research in the field of stem cell development and differentiation in the next decade will try to find some answers.

Adolescent↗
PubMed2006

[Inhibitory effect of murine cytomegalovirus infection on neural stem cells' differentiation and its mechanisms].

OBJECTIVE: Cytomegalovirus (CMV) is the leading infectious cause of congenital anomalies of the central nervous system caused by intrauterine infection. However, the exact pathogenesis of these brain abnormalities has not been fully elucidated. It has been reported that periependymitis, periventricular necrosis and calcification are the most frequent findings in the brains of congenital CMV infection. Because a number of multipotential neural stem cells (NSCs) have been identified from ventricular zone, it is possible that NSCs in this area are primary targets for viral infection, which seems to be primarily responsible for the generation of the brain abnormalities. Therefore, the objective of the present study was to investigate the effect and mechanism of murine cytomegalovirus (MCMV) infection on neural stem cells' differentiation in vitro and its role in the mechanisms of brain abnormalities caused by congenital cytomegalovirus infection. METHODS: NSCs were prepared from fetal BALB/c mouse and were infected with recombinant MCMV RM461 inserted with a report gene LacZ at 1 multiplicity of infection (MOI = 1). The effect of MCMV infection on neural stem cells' differentiation was observed by detecting the ratio of nestin, GFAP and NSE positive cells with immunohistochemistry and flow cytometry on day 2 postinfection. The effects of MCMV infection on gene expression of Wnt-1 and neurogenin 1 (Ngn1) related to neural differentiation were detected by RT-PCR. RESULTS: NSCs isolated from embryonic mouse brains strongly expressed nestin, a specific marker of NSCs and had the capacity to differentiate into NF-200 and NSE positive neurons or GFAP positive astrocytes. At MOI = 1, the results of flow cytometry assay showed that nestin positive cells' proportion in the infection group [(62.2 +/- 1.8)%] was higher than that in the normal group [(37.2 +/- 2.4)%] (t = 4.62, P < 0.01). At the same time, the rates of GFAP and NSE positive cells' in the infection group were significantly lower than those in the normal group (P < 0.01). The scanning densities of Wnt-1 was 0.14 +/- 0.03 in the infection group while 0.32 +/- 0.04 in the control group (t = 7.21, P < 0.01). The scanning densities of Ngn1 were 0.09 +/- 0.01 and 0.21 +/- 0.02 in the two groups (t = 10.7, P < 0.01). CONCLUSIONS: These results suggest that MCMV infection could inhibit neuronal differentiation, which may be primary causes of disorders of brain development in congenital CMV infection. The decreased expression of Wnt-1 and Ngn1 may be involved in the inhibitory effect of murine cytomegalovirus infection on neural stem cells' differentiation, which may lead to a new strategy for preventing and treating brain abnormalities caused by CMV infection through regulating these two signal pathways.

Animals↗
PubMed2004

Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death.

The mechanisms that control neural stem and progenitor cell survival are unknown. In several pathological conditions, death receptor (DR) ligands and inflammatory cytokines exert a deleterious effect on neurons, whereas primitive neural cells migrate and survive in the site of lesion. Here, we show that even in the presence of inflammatory cytokines, DRs are unable to generate death signals in primitive neural cells. Neural stem and progenitor cells did not express caspase 8, the presence of which is required for initiating the caspase cascade. However, exogenous or cytokine-mediated expression of caspase 8 was not sufficient to restore their DR sensitivity. Searching for molecules potentially able to block DR death-inducing signaling complex (DISC), we found that primitive neural cells expressed high levels of the death effector domain-containing protein PED (also known as PEA-15). PED localized in the DISC and prevented caspase 8 recruitment and activation. Moreover, lentiviral-mediated delivery of PED antisense DNA resulted in dramatic down-regulation of the endogenous gene expression and sensitization of primitive neural cells to apoptosis mediated by inflammatory cytokines and DRs. Thus, absence of caspase 8 and high expression of PED constitute two levels of protection from apoptosis induced by DRs and inflammatory cytokines in neural stem and progenitor cells.

Apoptosis↗
PubMed2004

Expression of the polycomb group gene bmi-1 in the early chick embryo.

Bmi-1 is a protooncogene of the polycomb group that has important functions in self-renewal of adult stem cells and maintenance of anterior identity along the embryonic body axis. Despite these important functions, surprisingly little is known about its distribution pattern in the embryo. Here, we have isolated the chick homologue of bmi-1 and examined its expression pattern from gastrulation through neurulation and establishment of organ rudiments. During gastrulation, bmi-1 transcripts were expressed in the epiblast cells adjacent to the primitive streak. During early nervous system development, robust expression was observed in the open neural plate and later in the dorsal neural tube and much of the brain. Bmi-1 expression was also present in the developing heart primordia and the sensory placodes. The data show that bmi-1 is present in, but not restricted to, tissue containing multipotent precursor cells.

Amino Acid Sequence↗