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PubMed2006

Glucose-induced replicative senescence in mesenchymal stem cells.

Mesenchymal stem cells (MSCs) show great promise for use in a variety of cell-based therapies. Because isolated primary mesenchymal stem cells are low in numbers, in vitro expansion is necessary. However, the expansion potential is limited and in vitro aging leads to loss of multipotency and replicative senescence. Stress induced by culture conditions is likely to be a major cause of replicative senescence and reduced multipotency of MSC and optimization of culture conditions might be able to reduce this. Caloric restriction (CR) is the only established method to delay aging and extend lifespan. In vitro caloric restriction experiments are rare, but have demonstrated beneficial effects. Therefore, we investigated the effect of culture medium glucose concentration on the proliferative and differentiation potential of mesenchymal stem cells. Reduction in glucose concentrations led to decreased apoptosis and an increased rate of MSC proliferation and increased the number and size of fibroblastic colonies in the colony-forming unit assay.

Animals↗
PubMedDate not supplied

[The stem-cell reserve of the liver].

This paper considers the problem of epithelial stem cells of the liver and possibilities of its experimental solution. Authors' own data obtained with the model of induced hepatocarcinogenesis in mice are discussed; the experiments were performed using electron microscopy, autoradiography and immunochemistry. In accordance with these data, Gering cells are stem cells of the liver, and oval cells correspond to committed precursors capable to differentiation in either hepatocellular or cholangiolar direction under the conditions of periportal microenvironment. We have also compared hepatocyte differentiation in preneoplastic mouse liver and regenerating pancreas of adult rats (Rao et al. Amer. J. Pathol. 1989. V. 134. P. 1069-1086). We also discuss stem cell compartment organization in organs having glandular structure and the possibility of existence in the adult of non-committed multipotent cells capable of producing various types of differentiation in tissues having common origin during embryogenesis.

Animals↗
PubMedDate not supplied

Antigenic profiles of endothelial and hemopoietic lineages in murine intraembryonic hemogenic sites.

Two hemogenic sites are present in mouse embryos before the onset of fetal liver hemopoiesis. While the yolk sac provides for immediate erythropoiesis, an intraembryonic region encompassing the dorsal aorta produces definitive hematopoietic stem cells, as shown experimentally. At early developmental stages this region, that we named paraaortic splanchnopleura, produces multipotent progenitors. At the time of fetal liver colonisation, the paraaortic splanchnopleura further evolves into aorta, gonads and mesonephros (AGM) and contains progenitors capable of long term multilineage reconstitution. Only then are cytologically identifiable collections of early hemopoietic cells present in various arteries and in the mesentery. The present report focuses on the antigenic characterisation of immature hemopoietic progenitors in order to trace back the intraembryonic precursors at earlier developmental stages. CD34, an antigen expressed by immature progenitors and endothelial cells, labels all potential hemopoietic sites. Markers, supposed to counterstain endothelial cells and spare CD34+ hemopoietic cells, also stain various hemopoietic cells. The meaning of these shared antigenic expressions between cells of the endothelial and hemopoietic lineages in the early embryo is discussed.

Animals↗
PubMed2003

Copernican stem cells: regulatory constellations in adult hippocampal neurogenesis.

In the adult, neurogenesis occurs where constellations of signaling molecules are correctly orchestrated and where competent cells are present to interpret these signals. As the instruments used to observe adult neurogenesis become more sophisticated, the concept of a discrete competent "stem cell" has become less concrete. Neural progenitor cells once thought committed to a single lineage can be influenced to become multipotent and somatic tissues appear to yield cells capable of tremendous peripheral and central lineage potential. The variety of cell types that appear competent to generate neurons suggests that the "Hilios" of adult neurogenesis may not necessarily be a single cellular entity but rather the sum of signals that dictate, "Make a new neuron here." These signals may not be limited to the recruitment of preexisting neural stem cells but may also, in some subtle way, reprogram local precursors to create "stem-like cells," where needed.

Animals↗
PubMed2004

Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice.

The t(12;21) translocation, which generates the TEL-AML1 (ETV6-RUNX1) fusion gene, is the most common structural chromosome change in childhood cancer and is exclusively associated with the common B cell precursor subset of acute lymphoblastic leukemia (ALL). Evidence suggests that the translocation usually occurs in utero during fetal hemopoiesis and most probably constitutes an initiating or first-hit mutation that is necessary but insufficient for the development of overt, clinical leukemia. The mechanism by which TEL-AML1 contributes to this early stage of leukemogenesis is unknown. To address this question we have analyzed hemopoiesis in mice syngeneically transplanted with TEL-AML1-transduced bone marrow stem cells. TEL-AML1 expression was associated with an accumulation/expansion of primitive c-kit-positive multipotent progenitors and a modest increase in myeloid colony-forming cells. TEL-AML1 expression was, however, permissive for myeloid differentiation. Analysis of B lymphopoiesis revealed an increase in early, pro-B cells but a differentiation deficit beyond that stage, resulting in reduced B cell production in the marrow. TEL-AML1-positive B cell progenitors exhibited reduced expression of the surrogate light-chain component lambda5 and the IL-7 receptor, both of which may contribute to impedance of differentiation in vivo and account for their reduced in vitro clonogenicity in IL-7. A selective differentiation deficit of B lineage progenitors (i) is consistent with the phenotype of TEL-AML1-associated leukemia in children and (ii) provides a potential mechanism for the protracted preleukemic state that often precedes ALL. These results provide mechanistic insight into the role of the t(12;21) translocation in the initiation of common B cell precursor ALL.

Animals↗
PubMed2002

The effect of thrombopoietin on erythroid progenitors in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare congenital red blood cell aplasia. Usually, erythropoiesis in vitro is defective, and decreased numbers of erythroid progenitors are found in colony assays performed with bone marrow cells. Recently, some investigators showed that thrombopoietin (TPO) also works on common multipotent progenitor cells and stimulates erythropoiesis. We examined the effect of TPO together with erythropoietin (EPO), stem cell factor (SCF), and/or interleukin-3 (IL-3) on erythroid burst-forming units (BFU-E) of bone marrow nonadherent mononuclear cells from 2 patients with DBA using a serum-free culture system. Very few BFU-E appeared in cultures containing EPO alone. Adding IL-3, SCF, or both to cultures containing EPO induced an increase in the number of BFU-E. When TPO was added to cultures containing EPO and IL-3, SCF, or both, the number of BFU-E further increased. Especially in patient 2, BFU-E formation was grossly equal to that in normal controls. We conclude that TPO enhances bone marrow erythropoiesis in patients with DBA in the presence of EPO and SCF and/or IL-3. The data raise the possibility of the combination of TPO and SCF as a therapeutic agent in DBA.

Anemia, Diamond-Blackfan↗
PubMed2005

Inhibition of AF116909 gene expression enhances the differentiation of neural stem cells.

OBJECTIVES: Neural stem cells (NSCs) are self-renewed, pluripotent cells that can differentiate into neurons, astrocytes and oligodendrocytes. Such multipotency that allows production of specific types of nerve cells for basic research and therapeutic purposes depends on how these cells are directed in their differentiation. Here, we investigate the function of the AF116909 gene in the differentiation of NSC. METHODS: NSC culture was isolated from the striatum corpora of embryonic brain tissues in a 14-day pregnant rat. A constructed RNAi (RNA-mediated interference) vector was transfected to knock down the expression of this gene. Afterwards, RT-PCT was applied to examine the presence of endogenous AF116909 mRNA and the effect of RNA interference. RESULTS: After the knockdown of this gene, we detected that the differentiation rate of cells was enhanced to 80% on the 11th day in comparison with 12% in the control cells transfected with the expression vector alone. DISCUSSION: These findings suggest that AF116909 functions in inhibiting the differentiation of NSCs, and AF116909 gene-targeting by RNAi provides a useful method to study the differentiation mechanisms of NSCs.

Animals↗
PubMed2000

Circulating hematopoietic progenitor cells in first trimester fetal blood.

The yolk sac and aorto-gonad-mesonephros region are well recognized as the principal sites of hematopoiesis in the developing embryo, and the liver is the principal site of hematopoiesis in the fetus. However, little is known about circulating hematopoietic stem and progenitor cells in early fetal life. We investigated the number and characteristics of circulating progenitors in first trimester blood of 64 human fetuses (median gestational age, 10(+4) weeks; range, 7(+6)-13(+6) weeks). CD34+ cells accounted for 5.1 +/- 1.0% of CD45+ cells in first trimester blood, which is significantly more than in term cord blood (0.4 +/- 0.03%; P =.0015). However, the concentration of CD34+ cells (6.6 +/- 2.4 x 10(4)/mL) was similar to that in term cord blood (5.6 +/- 3.9 x 10(4)/mL). The total number of progenitors cultured from unsorted mononuclear cells (MNCs) in first trimester blood was 19.2 +/- 2.1 x 10(3)/mL, which is similar to that in term cord blood (26.4 +/- 5.6 x 10(3)/mL). All lineages were seen: colony-forming unit-GEMM (CFU-GEMM), CFU-GM, BFU-e, BFU-MK, and CFU-MK. Clonogenic assays of CD34+ cells purified from first trimester samples produced mainly two lineages: BFU-e (39.0 +/- 9.6 x 10(3)/mL CD34+ cells) and CFU-GEMM (22.6 +/- 4.7 x 10(3)/mL CD34+ cells). Short-term liquid culture of first trimester blood MNCs in SCF + IL-3 + Flt-3 (stem cell factor + interleukin-3 + Flt-3) increased, by 7-fold, the numbers of CFU-GEMM and induced a dramatic increase in BFU-e (65.6 +/- 12.1-fold). These data show that significant numbers of committed and multipotent progenitors with capacity for expansion circulate in first trimester fetal blood and can be CD34 selected. These cells should be suitable targets for gene transfer and stem cell transplantation and, because fetal hematopoietic progenitors have been demonstrated in the maternal circulation from early gestation, may also be manipulated for noninvasive prenatal diagnosis of major genetic disorders. (Blood. 2000;95:1967-1972)

Antigens, CD34↗
PubMed2001

Broad distribution of colony-forming cells with erythroid, myeloid, dendritic cell, and NK cell potential among CD34(++) fetal liver cells.

The generation of erythroid, myeloid, and lymphoid cells from human fetal liver progenitors was studied in colony-forming cell (CFC) assays. CD38(-) and CD38(+) progenitors that expressed high levels of CD34 were grown in serum-deprived medium supplemented with kit ligand, flk2/flt3 ligand, GM-CSF, c-mpl ligand, erythropoietin, and IL-15. The resulting colonies were individually analyzed by flow cytometry. CD56(+) NK cells were detected in 21.9 and 9.9% of colonies grown from CD38(-) and CD38(+) progenitors, respectively. NK cells were detected in mostly large CD14(+)/CD15(+) myeloid colonies that also, in some cases, contained red cells. NK cells were rarely detected in erythroid colonies, suggesting an early split between the erythroid and the NK cell lineages. CD1a(+) dendritic cells were also present in three-quarters of the colonies grown from CD38(-) and CD38(+) progenitors. Multilineage colonies containing erythrocytes, myeloid cells, and NK cells were present in 13.7 and 2.7% of colonies grown from CD38(-) and CD38(+) progenitors, respectively. High proliferative-potential CFCs that generated multilineage colonies were also detected among both populations of progenitors. The total number of high proliferative-potential CFCs with erythroid, myeloid, and NK cell potential was estimated to be 2-fold higher in the CD38(+) fraction compared with the CD38(-) fraction because of the higher frequency of CD38(+) cells among CD34(++) cells. The broad distribution of multipotent CFCs among CD38(-) and CD38(+) progenitors suggests that the segregation of the erythroid, myeloid, and lymphoid lineages may not always be an early event in hemopoiesis. Alternatively, some stem cells may be present among CD38(+) cells.

ADP-ribosyl Cyclase↗
PubMed2006

Vascular cells.

Embryonic stem (ES) cells are cells derived from the inner cell mass of a blastocyst stage embryo. These self-renewing multipotent cells are able to differentiate to the three embryonic germ layers, the endoderm, ectoderm, and mesoderm, and are thus able to produce virtually all cell types. The ES cell capacity to generate various cell types has been studied extensively, and exploitation of ES cell characteristics allowed the production of several differentiated cell types of multiple tissues. Moreover, the process of ES cell differentiation provides a unique opportunity to observe early embryonic developmental events that are unattainable in the embryo itself. This chapter addresses the in vitro differentiation procedure of endothelial and vascular smooth muscle cells from human ES cells, with reference to similar studies performed in mouse and nonhuman primate ES cells, and provides several tools for the detailed characterization of differentiated cells.

Animals↗
PubMed2002

Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice.

The adaptor protein Lnk, and the closely related proteins APS and SH2B, form a subfamily of SH2 domain-containing proteins implicated in growth factor, cytokine, and immunoreceptor signaling. To elucidate the physiological function of Lnk, we derived Lnk-deficient mice. Lnk(-/-) mice are viable, but display marked changes in the hematopoietic compartment, including splenomegaly and abnormal lymphoid and myeloid homeostasis. The in vitro proliferative capacity and absolute numbers of hematopoietic progenitors from Lnk(-/-) mice are greatly increased, in part due to hypersensitivity to several cytokines. Moreover, an increased synergy between stem cell factor and either interleukin (IL)-3 or IL-7 was observed in Lnk(-/-) cells. Furthermore, Lnk inactivation causes abnormal modulation of IL-3 and stem cell factor-mediated signaling pathways. Consistent with these results, we also show that Lnk is highly expressed in multipotent cells and committed precursors in the erythroid, megakaryocyte, and myeloid lineages. These data implicate Lnk as playing an important role in hematopoiesis and in the regulation of growth factor and cytokine receptor-mediated signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells.

Telomere length must be tightly regulated in highly proliferative tissues, such as the lymphohematopoietic system. Under steady-state conditions, the levels and functionality of hematopoietic-committed or multipotent progenitors were not affected in late-generation telomerase-deficient mice (mTerc(-/-)) with critically short telomeres. Evaluation of self-renewal potential of mTerc(-/-) day-12 spleen colony-forming units demonstrated no alteration as compared with wildtype progenitors. However, the replating ability of mTerc(-/-) granulocyte-macrophage CFUs (CFU-GMs) was greatly reduced as compared with wildtype CFU-GMs, indicating a diminished capacity of late-generation mTerc(-/-) committed progenitors when forced to proliferate. Long-term bone marrow cultures of mTerc(-/-) bone marrow (BM) cells show a reduction in proliferative capacity; this defect can be mainly attributed to the hematopoietic, not to the stromal, mTerc(-/-) cells. In serial and competitive transplantations, mTerc(-/-) BM stem cells show reduced long-term repopulating capacity, concomitant with an increase in genetic instability compared with wildtype cells. Nevertheless, in competitive transplantations late-generation mTerc(-/-) precursors can occasionally overcome this proliferative impairment and reconstitute irradiated recipients. In summary, our results demonstrate that late-generation mTerc(-/-) BM cells with short telomeres, although exhibiting reduced proliferation ability and reduced long-term repopulating capacity, can still reconstitute myeloablated animals maintaining stem cell function.

Animals↗
PubMed2000

Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate.

P210 Bcr-Abl is an activated tyrosine kinase oncogene encoded by the Philadelphia chromosome associated with human chronic myelogenous leukemia (CML). The disease represents a clonal disorder arising in the pluripotent hematopoietic stem cell. During the chronic phase, patients present with a dramatic expansion of myeloid cells and a mild anemia. Retroviral gene transfer and transgenic expression in rodents have demonstrated the ability of Bcr-Abl to induce various types of leukemia. However, study of human CML or rodent models has not determined the direct and immediate effects of Bcr-Abl on hematopoietic cells from those requiring secondary genetic or epigenetic changes selected during the pathogenic process. We utilized tetracycline-regulated expression of Bcr-Abl from a promoter engineered for robust expression in primitive stem cells through multilineage blood cell development in combination with the in vitro differentiation of embryonal stem cells into hematopoietic elements. Our results demonstrate that Bcr-Abl expression alone is sufficient to increase the number of multipotent and myeloid lineage committed progenitors in a dose-dependent manner while suppressing the development of committed erythroid progenitors. These effects are reversible upon extinguishing Bcr-Abl expression. These findings are consistent with Bcr-Abl being the sole genetic change needed for the establishment of the chronic phase of CML and provide a powerful system for the analysis of any genetic change that alters cell growth and lineage choices of the hematopoietic stem cell.

Animals↗
PubMed2006

Neural stem cell model for prion propagation.

The study of prion transmission and targeting is a major scientific issue with important consequences for public health. Only a few cell culture systems that are able to convert the cellular isoform of the prion protein into the pathologic scrapie isoform of the prion protein (PrP(Sc)) have been described. We hypothesized that central nervous system neural stem cells (NSCs) could be the basis of a new cell culture model permissive to prion infection. Here, we report that monolayers of differentiated fetal NSCs and adult multipotent progenitor cells isolated from mice were able to propagate prions. We also demonstrated the large influence of neural cell fate on the production of PrP(Sc), allowing the molecular study of prion neuronal targeting in relation with strain differences. This new stem cell-based model, which is applicable to different species and to transgenic mice, will allow thoughtful investigations of the molecular basis of prion diseases, and will open new avenues for diagnostic and therapeutic research.

Animals↗
PubMed2002

Membrane-bound neuregulin1 type III actively promotes Schwann cell differentiation of multipotent Progenitor cells.

Many steps of peripheral glia development appear to be regulated by neuregulin1 (NRG1) signaling but the exact roles of the different NRG1 isoforms in these processes remain to be determined. While glial growth factor 2 (GGF2), a NRG1 type II isoform, is able to induce a satellite glial fate in neural crest stem cells, targeted mutations in mice have revealed a prominent role of NRG1 type III isoforms in supporting survival of Schwann cells at early developmental stages. Here, we investigated the role of NRG1 isoforms in the differentiation of Schwann cells from neural crest-derived progenitor cells. In multipotent cells isolated from dorsal root ganglia, soluble NRG1 isoforms do not promote Schwann cell features, whereas signaling by membrane-associated NRG1 type III induces the expression of the Schwann cell markers Oct-6/SCIP and S100 in neighboring cells, independent of survival. Thus, axon-bound NRG1 might actively promote both Schwann cell survival and differentiation.

Animals↗
PubMed1997

Enhanced maintenance and retroviral transduction of primitive hematopoietic progenitor cells using a novel three-dimensional culture system.

Current techniques for the in vitro maintenance of hematopoietic stem cells often lead to loss of pluripotency. Overcoming the technical difficulties that result in alterations in stem cells in vitro has important implications for areas of basic science and clinical medicine such as cell expansion, bone marrow transplantation and gene therapy. Recent insights into hematopoietic stem cell biology have demonstrated that the three-dimensional architecture of the culture environment may influence the maintenance of stem cell pluripotency in vitro. An intriguing hypothesis is that the utilization of three-dimensional culture systems may improve the maintenance and manipulation of these cells in vitro. We report that a novel, three-dimensional, tantalum-coated porous biomaterial (TCPB) may be employed effectively as a hematopoietic progenitor cell culture device that offers distinct advantages over conventional culture systems. Specifically, we demonstrate that the use of TCPB for culturing hematopoietic progenitor cells in the absence of exogenous cytokines results in enhanced hematopoietic progenitor cell survival, improved maintenance of the immature CD34+/38- phenotype, and improved retroviral transduction of CD34+ cells and long-term culture initiating cells (LTCIC), without compromising multipotency, as compared with cultures in plastic dishes or bone marrow stroma. These findings suggest that this three-dimensional culture system may be useful in advancing the in vitro culture and transduction of hematopoietic stem and progenitor cells.

Animals↗
PubMed2004

Adult stem cells.

Development of a multicellular organism is accomplished through a series of events that are preprogrammed in the genome. These events encompass cellular proliferation, lineage commitment, lineage progression, lineage expression, cellular inhibition, and regulated apoptosis. The sequential progression of cells through these events results in the formation of the differentiated cells, tissues, and organs that constitute an individual. Although most cells progress through this sequence during development, a few cells leave the developmental continuum to become reserve precursor cells. The reserve precursor cells are involved in the continual maintenance and repair of the tissues and organs throughout the life span of the individual. Until recently it was generally assumed that the precursor cells in postnatal individuals were limited to lineage-committed progenitor cells specific for various tissues. However, studies by Young, his colleagues, and others have demonstrated the presence of two categories of precursor cells that reside within the organs and tissues of postnatal animals. These two categories of precursor cells are lineage-committed (multipotent, tripotent, bipotent, and unipotent) progenitor cells and lineage-uncommitted pluripotent (epiblastic-like, ectodermal, mesodermal, and endodermal) stem cells. These reserve precursor cells provide for the continual maintenance and repair of the organism after birth.

Adult↗
PubMed1993

Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors.

In the absence of growth factors, hemopoietic cells die rapidly by the process of apoptosis. Transfection of the human bcl-2 gene into an interleukin-3 (IL-3)-dependent, multipotent hemopoietic cell line allowed these cells to survive in the absence of IL-3, both in serum-containing and serum-deprived conditions, and this survival was accompanied by multilineage differentiation. Moreover, single cell experiments showed that differentiation could occur in the absence of cell division. While these data do not rule out the possibility that growth factors can influence the lineage choice of multipotent cells, they suggest that exposure to growth factors may not be obligatory for the differentiation of stem cells. The data also support the hypothesis that differentiation is intrinsically determined and that the role of the hemopoietic growth factors is enabling rather than inductive.

Animals↗