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PubMed2005

Specification and patterning of neural crest cells during craniofacial development.

Craniofacial evolution is considered fundamental to the origin of vertebrates and central to this process was the formation of a migratory, multipotent cell population known as the neural crest. The number of cell types that arise from the neural crest is truly astonishing as is the number of tissues and organs to which the neural crest contributes. In addition to forming melanocytes as well as many neurons and glia in the peripheral nervous system, neural crest cells also contribute much of the cartilage, bone and connective tissue of the face. These multipotent migrating cells are capable of self renewing decisions and based upon these criteria are often considered stem cells or stem cell-like. Rapid advances in our understanding of neural crest cell patterning continue to shape our appreciation of the evolution of neural crest cells and their impact on vertebrate craniofacial morphogenesis.

Animals↗
PubMed2000

The splanchnopleura/AGM region is the prime site for the generation of multipotent hemopoietic precursors, in the mouse embryo.

The first hemopoietic cells were found in the yolk sac of mammalian embryos. Based on this observation it was postulated that hemopoietic stem cells are generated in this location. In the last few years, however, increasing evidence indicates that there is an independent site of hemopoietic cell generation, in the embryo proper, designated the paraaortic splanchnopleura/aorta, gonad, mesonephros region. Precursors of hemopoietic cells are found in this region before circulation is established between the yolk sac and the embryo proper. In contrast to the hemopoietic cells found in the yolk sac, the ones found in the embryo proper are multipotent lympho-myeloid precursors that rapidly acquire the capacity to reconstitute the hemopoietic system of adult irradiated recipients. We propose that these are the founder cells of adult definitive hematopoiesis.

Animals↗
PubMedDate not supplied

Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome.

The cellular events that lead to transient myeloproliferative syndrome (TMS) in patients with trisomy 21 mosaicism confined to the hematopoietic system are poorly understood. The authors attempt to define the event that led to the development of TMS in a single patient with clonal trisomy 21. A phenotypically normal neonate with clonal trisomy 21 is described. At the time when his TMS was resolving, fluorescent in situ hybridization analysis was performed on cell populations sorted by flow cytometry to determine what cell populations contained trisomic cells. Trisomy 21 was found in cells of the erythrocytic and monocytic lineages, but not in the stem cells, progenitor compartment, megakaryocytes, lymphocytes, or neutrophils. These results support the hypothesis that, in this neonate, trisomy 21 occurred in a multipotent hematopoietic progenitor, and a subsequent event led to the appearance of the blast population.

Adult↗
PubMed1996

Hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood progenitor cells evaluated in vitro and in vivo.

The hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood (UCB) samples was evaluated in vitro and in vivo. Phenotypic analysis shows that approximately 1% of cord blood mononuclear cells express high levels of CD34 antigen on their surface (CD34hi), but none of a panel of lineage antigens (Lin-), suggesting that they are hematopoietic progenitor cells that have not yet committed to a specific lineage. Approximately 1% of CD34hi/Lin- cells are primitive hematopoietic progenitors that produce B lymphoid and multiple myeloid progeny for up to 7 weeks in stromal cell cultures. Twenty-one percent (+/- 13%) of CD34hi/Lin- cells also express low levels of the Thy-1 antigen and are threefold to fourfold enriched over CD34hi/Lin- cells in primitive hematopoietic potential as measured by long-term culture and phenotypic analysis. One-week liquid cultures of CD34-enriched UCB progenitor cells in the presence of interleukin (IL)-3, IL-6, and stem cell factor (SCF) results in a two-fold to threefold expansion of progenitors capable of reinitiating long-term stromal cell cultures. Only the CD34hi/Thy-1+/Lin- cell population was capable of maintaining progenitors with secondary transfer potential in long-term stromal cell cultures and is thus postulated to contain all of the primitive hematopoietic stem cells in UCB. The in vivo transplantation potential of UCB was also measured. Ex vivo manipulated UCB progenitor cells were used to engraft irradiated human thymus fragments implanted in severe combined immunodeficiency (SCID) mice. Thymic engraftment with >5% donor-derived cells and a normal CD4/CD8 distribution was observed in 19 of 23 tissues tested. UCB cells from in vitro expansion cultures engrafted with efficiencies comparable to nonexpanded cells. Similar results were obtained for UCB engraftment of human bone fragments implanted in SCID mice. In all cases, engraftment was achieved in competition with endogenous competitor stem cells and across major histocompatibility barriers. Taken together, this data demonstrates that human UCB is a rich source of multipotent hematopoietic progenitors that can be cryopreserved, enriched by physical methods, and expanded in a limited fashion without measurable loss of long-term culture or in vivo engrafting potential as measured in these assays.

Animals↗
PubMed2000

Multipotency of a bone marrow stromal cell line, TBR31-2, established from ts-SV40 T antigen gene transgenic mice.

Bone marrow is believed to contain multipotential stromal stem cells which can differentiate into osteoblasts, chondrocytes, adipocytes, and myoblasts (Prockop, D. J. Science 276, 71-74, 1997). Therefore, characterization and identification of the stem-like cell within the stromal cells are important to understand bone marrow function in relation to the hematopoietic microenvironment, and repair/regeneration of tissue defects. TBR31-2 cell, a bone marrow stromal cell line established from bone marrow of transgenic mice harboring temperature-sensitive (ts) simian virus (SV) 40T-antigen gene for immortality, is induced toward both adipocytic and osteogenic cells under conditions of the inactivation of T-antigen (Okuyama, R., Yanai, N., Obinata, M. Exp. Cell Res. 218, 424-429, 1995). In this work, using a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, mRNA expressions of tissue-specific differentiation markers for adipocyte (lipoprotein lipase), osteoblast (type I collagen and osteocalcin), chondrocyte (type II and X collagen), and muscle cell (desmin) were examined during a long-term culture of the cell. In addition, histochemical studies showed the appearance of adipocytic, osteoblastic, chondrocytic, and muscle cells during this long-term culture. Thus, TBR31-2, which has characteristics of an undifferentiated cell, has the potential to express the multipotential cell lineages. These results indicated that a multipotential progenitor cell including potential to differentiate into a muscle cell and which is situated in the mesenchymal cell lineage was first obtained.

Animals↗
PubMed2006

Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells.

OBJECTIVE: Muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle exhibit long-time proliferation, high self-renewal, and multipotent differentiation. This study was undertaken to investigate the ability of MDSCs that were retrovirally transduced to express bone morphogenetic protein 4 (BMP-4) to differentiate into chondrocytes in vitro and in vivo and enhance articular cartilage repair. METHODS: Using monolayer and micromass pellet culture systems, we evaluated the in vitro chondrogenic differentiation of LacZ- and BMP-4-transduced MDSCs with or without transforming growth factor beta1 (TGFbeta1) stimulation. We used a nude rat model of a full-thickness articular cartilage defect to assess the duration of LacZ transgene expression and evaluate the ability of transplanted cells to acquire a chondrocytic phenotype. We evaluated cartilage repair macroscopically and histologically 4, 8, 12, and 24 weeks after surgery, and performed histologic grading of the repaired tissues. RESULTS: BMP-4-expressing MDSCs acquired a chondrocytic phenotype in vitro more effectively than did MDSCs expressing only LacZ; the addition of TGFbeta1 did not alter chondrogenic differentiation of the BMP-4-transduced MDSCs. LacZ expression within the repaired tissue continued for up to 12 weeks. Four weeks after surgery, we detected donor cells that coexpressed beta-galactosidase and type II collagen. Histologic scoring of the defect sites 24 weeks after transplantation revealed significantly better cartilage repair in animals that received BMP-4-transduced MDSCs than in those that received MDSCs expressing only LacZ. CONCLUSION: Local delivery of BMP-4 by genetically engineered MDSCs enhanced chondrogenesis and significantly improved articular cartilage repair in rats.

Animals↗
PubMed2005

Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options.

The continuous regeneration of glial cells arising from endogenous stem cell populations in the central nervous system (CNS) occurs throughout life in mammals. In the ongoing research to apply stem cell therapy to neurological diseases, the capacity to harness the multipotential ability of endogenous stem cell populations has become apparent. Such cell populations proliferate in response to a variety of injury states in the CNS, but in the absence of a supportive microenvironment they contribute little to any significant behavioral recovery. In the authors' laboratory and elsewhere, recent research on the regenerative potential of these stem cells in disease states such as spinal cord injury has demonstrated that the cells' proliferative potential may be greatly upregulated in response to appropriate growth signals and exogenously applied trophic factors. Further understanding of the potential of such multipotent cells and the mechanisms responsible for creating a favorable microenvironment for them may lead to additional therapeutic alternatives in the setting of neurological diseases. These therapies would require no exogenous stem cell sources and thus would avoid the ethical and moral considerations regarding their use. In this review the authors provide a brief overview of the enhancement of endogenous stem cell proliferation following neurological insult.

Animals↗
PubMed2004

Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin.

Little is known about hematopoietic stem cell (HSC) development from mesoderm. To gain more information on the intraembryonic HSC site of origin, we purified multipotent hematopoietic progenitors from the aorta-gonads-mesonephros (AGM) of mice. This population, expressing c-Kit, AA4.1, CD31, and CD41, but not Flk1, and mainly negative for CD45, proved capable of long-term reconstitution in sublethally irradiated Rag2gammac(-/-) recipients. We assigned the expression of GATA-2, GATA-3, and lmo2 to AGM-HSC, whereas erythromyeloid progenitors express only GATA-2. This unique combination of surface markers and transcription factors could be allocated in the AGM to the intraaortic clusters and the subaortic patches underlying aortic endothelial cells. Taken together, those data indicate that embryonic HSCs (i) differ from their fetal liver and adult counterpart by the low expression of CD45, (ii) do not colocalize with aortic endothelial cells as previously thought, and (iii) are localized, at 10.5 days postcoitum, in the splanchnic mesoderm underlying aortic endothelial cells, within GATA-3(+)CD31(+) cell clusters.

Animals↗
PubMed2006

New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors.

A model of hematopoietic development wherein multipotentiality is conserved until segregation of myeloid and lymphoid potential has recently been challenged, proposing that megakaryocyte/erythrocyte (MegE) potential is lost in Flk2/Flt3-expressing early progenitors. Here, we used sensitive in vivo approaches to quantitatively and kinetically assess the MegE potential of hematopoietic stem cells and various Flk2(+) early progenitors and compared it with the MegE potential of downstream committed myeloid and lymphoid progenitors and with their ability to give rise to mature myelomonocytic and lymphoid cells. We demonstrate that Flk2(+) early progenitors retain MegE potential in vivo both at the population and clonal levels. These results indicate that Flk2 expression by early progenitors is not at the expense of full multipotency and support the current model of hematopoietic development with segregation of myeloid and lymphoid lineages from multipotent progenitors.

Animals↗
PubMed1985

Differentiation of mixed colony-forming cells in normal human bone marrow and blood.

In blood and marrow samples from ten normal adults, mixed colonies were found in agar cultures at concentrations of 4.1 +/- 3.4/10(5) mononuclear bone marrow cells, and of 4.7 +/- 4/5 X 10(5) mononuclear blood cells. Reseeding of five- to seven-day clusters of immature cells in fresh medium with 5% PHA leukocyte-conditioned medium (PHA-LCM) and 2 U erythropoietin (Epo) showed that 10(5) mononuclear cells contained as many as 42 +/- 12 CFU-mix in bone marrow and 12 +/- 7 CFU-mix in blood, i.e., ten times more than in the primary cultures. Attempts were made to discover why these potentially mixed colonies failed to develop in primary cultures. For this purpose five- to seven-day clusters of immature cells from cultures of 5 X 10(4) bone marrow cells grown with PHA-LCM, Epo, or both were reseeded in medium containing one or both stimulants. The presence of both in secondary culture gave the best CFU-mix growth, whatever the primary stimulation, i.e., more than one-third of the immature clusters gave rise to colonies of red cells and granulocyte lineages. The addition of one or both stimulants between days 7 and 14 of primary culture, however, did not increase the number of mixed colonies or give rise to late developing ones. Reseeding of colonies and clusters of 14-day primary cultures showed that at least one-third of erythroid bursts or of late-developing granulocyte colonies contained CFU-mix, but that less than 10% of 14-day clusters developed into mixed colonies. Cultures of nonadherent cells, mononuclear cells of less than 1.065/g density or with a velocity sedimentation rate of less than 6 mm/h gave the same results as the culture of total mononuclear cells; i.e., at least ten times more multipotent progenitors were found by reseeding after five to seven days than in primary cultures. We conclude that in human bone marrow and blood the physical and kinetic properties of pluripotent stem cells are similar to those of 14-day erythroid bursts and GM colonies. Under normal culture conditions, most of these cell types differentiate into one cell lineage only, and plurilineage differentiation is inhibited.

Blood Cell Count↗
PubMed1997

Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization.

We isolated hematopoietic stem cells (HSC) from mice treated with cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF). All mobilized multipotent progenitor activity was contained in two populations: Thy-1(lo) Sca-1+ Lin- Mac-1- CD4- c-kit+ long-term reconstituting progenitors and Thy-1(lo) Sca-1+ Lin- Mac-1(lo) CD4- transiently reconstituting progenitors. CY/G-CSF treatment drove both long-term and transient multipotent progenitors into cycle, leading to a more than 12-fold expansion in the number of long-term self-renewing HSC prior to mobilization. After CY and 2 days of G-CSF treatment the number of bone marrow HSC began to decline and the number of blood and splenic HSC increased. HSC continued to proliferate in the bone marrow and spleen through 8 days of G-CSF treatment, but HSC released into the blood tended to be in G0/G1 phase. Mobilized multipotent progenitors isolated from the spleen were less efficient than normal bone marrow multipotent progenitors in engrafting irradiated mice but did not differ in colony forming unit-spleen (CFU-S) activity or single cell in vitro assays of primitive progenitor activity. The data suggest that mobilized HSC isolated from the spleen are less efficient at homing to and engrafting the bone marrow of irradiated recipient mice.

Animals↗
PubMed2000

Incubation of murine bone marrow cells in hypoxia ensures the maintenance of marrow-repopulating ability together with the expansion of committed progenitors.

We developed previously a hypoxic culture system in which progenitors endowed with marrow-repopulating ability (MRA), unlike committed progenitors, were selected and maintained better than in air. We report here an improvement to this system targeted at combining the maintenance of progenitors sustaining MRA with the numerical expansion of multipotent and committed progenitors. Murine bone marrow cells were incubated at 1% oxygen in liquid medium supplemented with stem cell factor, granulocyte colony-stimulating factor, interleukin-6 and interleukin-3. In day 8 hypoxic cultures, the numbers of high proliferative potential and granulocyte/macrophage colony-forming cells (HPP-CFC and CFU-GM) were increased with respect to time zero. Colonies generated by HPP-CFC derived from hypoxic cultures exhibited a high replating ability, whereas colonies generated by HPP-CFC derived from control cultures exhibited a low replating ability. MRA was fully maintained in hypoxia and markedly reduced in air. Thus, severe hypoxia is able to ensure a full maintenance of progenitors sustaining MRA, together with a significant expansion of in vitro-detectable clonogenic progenitors, including those endowed with replating ability. This system could contribute to the improvement of current techniques for the in vitro treatment of human haematopoietic cell populations before transplantation.

Animals↗
PubMed2005

SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.

To improve our ability to identify hematopoietic stem cells (HSCs) and their localization in vivo, we compared the gene expression profiles of highly purified HSCs and non-self-renewing multipotent hematopoietic progenitors (MPPs). Cell surface receptors of the SLAM family, including CD150, CD244, and CD48, were differentially expressed among functionally distinct progenitors. HSCs were highly purified as CD150(+)CD244(-)CD48(-) cells while MPPs were CD244(+)CD150(-)CD48(-) and most restricted progenitors were CD48(+)CD244(+)CD150(-). The primitiveness of hematopoietic progenitors could thus be predicted based on the combination of SLAM family members they expressed. This is the first family of receptors whose combinatorial expression precisely distinguishes stem and progenitor cells. The ability to purify HSCs based on a simple combination of SLAM receptors allowed us to identify HSCs in tissue sections. Many HSCs were associated with sinusoidal endothelium in spleen and bone marrow, though some HSCs were associated with endosteum. HSCs thus occupy multiple niches, including sinusoidal endothelium in diverse tissues.

Animals↗
PubMed2005

Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells.

Mesenchymal stem cell (MSC) has drawn much attention in the aspect of tissue renewal and wound healing because of its multipotency. We initially observed that bone marrow-derived human MSCs (hMSCs) divided poorly and took flat and enlarged morphology after expanded in culture over a certain number of cell passage, which resembled characteristic features of senescent cells, well-studied in human diploid fibroblasts (HDFs). More interestingly, adipogenic differentiation potential of hMSCs sharply declined as they approached the end of their proliferative life span. In this study, altered hMSCs were verified to be senescent by their senescence-associated beta-galactosidase (SA-beta-gal) activity and the increased expression of cell cycle regulating proteins (p16(INK4a), p21(Waf1) and p53). Similar as in HDFs, basal phosphorylation level of ERK was also significantly increased in senescent hMSCs, implying altered signal paths commonly shared by the senescent cells. Insulin, a major component of adipogenesis inducing medium, did not phosphorylate ERK 1/2 more in senescent hMSCs after its addition whereas it did in young cells. In senescent hMSCs, we also found a significant increase of caveolin-1 expression, previously reported as a cause for the attenuated response to growth factors in senescent HDFs. When we overexpressed caveolin-1 in young hMSC, not only insulin signaling but also adipogenic differentiation was significantly suppressed with down-regulated PPARgamma2. These data indicate that loss of adipogenic differentiation potential in senescent hMSC is mediated by the over-expression of caveolin-1.

Adipocytes↗
PubMed1999

Gliogenesis depends on glide/gcm through asymmetric division of neuroglioblasts.

Some neurons and glial cells originate from neuroblasts and glioblasts, stem cells that delaminate from the ectoderm of developing fly embryos. A second class of glial cells and neurons differentiates from multipotent precursors, the neuroglioblasts. The differentiation of both glial cell types depends on glial cell deficient/glial cell missing (glide/gcm). Although it has been shown that this transcription factor promotes gliogenesis at the expense of neurogenesis, the cellular mechanisms underlying this fate choice are poorly understood. Using loss and gain of function glide/gcm mutations here we show that the cell fate choice takes place in the neuroglioblast, which divides and produces a glioblast and a neuroblast. Such choice requires the asymmetric distribution of glide/gcm RNA, which accumulates preferentially on one side of the neuroglioblast and is inherited by one cell, the presumptive glioblast. Interestingly, glial cells can differentiate from cells that delaminate as neuroglioblasts or they can arise from cells that start expressing glide/gcm several hours after delamination of a neuroblast. Altogether, these findings identify a novel type of asymmetric cell division and disclose the lineage relationships between glia and neurons. They also reveal the mode of action of the glide/gcm promoting factor.

Animals↗
PubMed1993

Bone marrow clones representing an intermediate stage of development between hematopoietic stem cells and pro-T-lymphocyte or pro-B-lymphocyte progenitors.

We have established in culture several nontransformed bone marrow clones (called PR) that show phenotypic and genotypic characteristics that distinguish them from totipotent stem cells and lineage-restricted Pro-T lymphocytes, Pro-B lymphocytes, and myeloid cell progenitors. In vivo and/or in vitro the PR clones give rise to T lymphocytes, B lymphocytes, and some myeloid-lineage cells, but they appear not to be able to generate cells of the erythroid lineage, nor can they rescue mice from a lethal dose of irradiation. We conclude that the PR clones are precursor cells representing an intermediate stage of development between the totipotential stem cell and lineage-restricted progenitor cells. The results described here support a model of blood cell formation in which stem cell differentiation is a progressive process marked by the stepwise loss of self renewal and functional potential. In addition, they provide evidence that cytokines and specialized microenvironments can direct the fate of the developing multipotent progenitor cells.

Animals↗
PubMed2006

FGF-4 regulates neural progenitor cell proliferation and neuronal differentiation.

The FGF-4 (fibroblast growth factor 4, known as HST-1) protein is an important mitogen for a variety of cell types. However, only limited information is available concerning tissue distribution and the biological role of FGF-4 in the brain. In situ hybridization analysis revealed localization of mouse Fgf-4 mRNA in the normal postnatal mouse hippocampus, subventricular zone (SVZ), and the rostral migratory stream where new neurons generate, migrate, and become incorporated into the functional circuitry of the brain. We also investigated whether FGF-4 could promote both proliferation and differentiation of the neural progenitor cells by using an in vitro neurosphere assay. The addition of recombinant FGF-4 generated large proliferative spheres that have a multipotent differentiation ability. Furthermore, recombinant FGF-4 significantly promotes neuronal differentiation in attached clonal neurosphere culture. These findings suggest that FGF-4 has an ability to promote neural stem cell proliferation and neuronal differentiation in the postnatal brain.

Animals↗