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Results for “Multipotent Stem Cells”

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PubMed1993

Production and characterization of lymphoblastoid cell lines with the paroxysmal nocturnal hemoglobinuria phenotype.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder caused by a somatic mutation in a hematopoietic stem cell. The fact that, in some cases, not only myeloid but also lymphoid cells are affected suggests that the mutation has occurred in a multipotent stem cell. By studying the expression of CD59 antigen (membrane inhibitor of reactive lysis) and of decay accelerating factor (DAF) on the lymphocytes of 16 patients with PNH, we found an abnormal population of lymphocytes (with absent CD59 and DAF) in 10 cases. From 4 of these patients we were able to produce Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCLs) that have a PNH phenotype (absent CD59, DAF, and CD48). PNH LCL cells have apparently normal DAF messenger RNA despite not having DAF on their surface. These cell lines will be a valuable resource for further investigation of the defect or defects underlying PNH.

Adult↗

PubMed1982

Testosterone and synthetic and androgens improve the in vitro survival of human marrow progenitor cells in serum-free suspension cultures.

The direct effect of testosterone and its synthetic analogs on the maintenance of human erythroid progenitor cells (BFU-E) and GM-CFC was studied in suspension cultures. To avoid interference by serum components, the experiments were conducted in serum-free media containing insulin, transferrin, selenium, BSA, and alpha-thioglycerol. When added at concentrations between 10(-7)M and 10(-9)M, testosterone improved survival of BFU-E and GM-CFC. Of the nine analogs tested, eight improved BFU-E maintenance in vitro: nandrolone norethandrolone, and oxymetholone were most active, whereas etiocholanolone had only marginal effects. The influence of these compounds on GM-CFC was less pronounced, with testosterone showing the highest activity. It is concluded that testosterone and some of the synthetic analogs tested exert their hemopoietic effect, at least partly, by affecting the maintenance of erythroid and granulocytic stem cells, directly by increasing their survival or proliferation or indirectly by increasing the input from multipotent stem cell pool, or by both mechanisms.

Cell Count↗

PubMed2000

Gliogenesis in the central nervous system.

Multipotential neuroepithelial stem cells are thought to give rise to all the differentiated cells of the central nervous system (CNS). The developmental potential of these multipotent stem cells becomes more restricted as they differentiate into progressively more committed cells and ultimately into mature neurons and glia. In studying gliogenesis, the optic nerve and spinal cord have become invaluable models and the progressive stages of differentiation are being clarified. Multiple classes of glial precursors termed glial restricted precursors (GRP), oligospheres, oligodendrocyte-type2 astrocyte (O-2A) and astrocyte precursor cells (APC) have been identified. Similar classes of precursor cells can be isolated from human neural stem cell cultures and from embryonic stem (ES) cell cultures providing a non-fetal source of such cells. In this review, we discuss gliogenesis, glial stem cells, putative relationships of these cells to each other, factors implicated in gliogenesis, and therapeutic applications of glial precursors.

Animals↗

PubMed1993

Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice.

Lethally irradiated mice reconstituted with bone marrow expressing P210 BCR-ABL can develop myeloproliferative syndromes that resemble the initial phase of human chronic myelogenous leukemia (CML). Mice that develop the CML-like syndrome can be segregated into two groups based on the latency with which the granulocytic disease appears--early onset (< 20 weeks) and late onset (> 20 weeks). Only cells from mice exhibiting the late-onset CML-like syndrome can efficiently propagate the disease when transplanted into sublethally irradiated syngeneic recipients. Mice engrafted with late-onset murine CML cells develop a range of hematopoietic disorders that originate from multipotent stem cells. The chronic granulocytic hyperplasia can be propagated by serial transplantation into secondary and tertiary recipient mice. The majority of transplanted mice succumb to acute myeloid and B- and T-lymphoid leukemias. These data support the idea that late-onset murine CML originates from a multipotent progenitor cell with a high replicating capacity. The inability to transplant the disease from mice developing the early-onset CML-like syndrome suggests that this disorder may originate from more differentiated progenitor cells with limited replication capacity that have undergone clonal expansion but are not immortalized. Although both early- and late-onset CML-like syndromes exhibit granulocytic hyperplasia, these disorders represent distinct diseases that appear to originate from different hematopoietic cell types. The late-onset CML-like disease and transfer to secondary recipients provides a useful murine model with features of the chronic and acute phases of human CML.

Animals↗

PubMed1992

IL-3 stimulated haemopoietic stem cell proliferation: evidence for G protein independent mitogenic signalling events.

Interleukin-3 stimulates the survival and proliferation of the FDCP-Mix 1 multipotent stem cell line. We have investigated the possible involvement of a guanyl nucleotide regulatory (G) protein(s) in the IL-3 stimulated proliferative response. We report here that pertussis toxin (PT) can partially inhibit IL-3 stimulated DNA synthesis and that this inhibition is bypassed by TPA. The ADP-ribosylation of the PT substrate G protein in vivo is complete in 2 hours without concomitant inhibition of IL-3 stimulated hexose transport or Na+/H+ exchange. When loaded into FDCP-Mix 1 cells fluoroaluminate and GTP-gamma-S, which can directly activate G proteins, are not capable of mimicking the effects of IL-3. Evidence is also presented that IL-3 does not stimulate a membrane-bound high affinity GTPase activity in the FDCP-Mix 1 cell line. These data suggest that a PT substrate G protein(s) can influence the IL-3 signalling cascade in an indirect or permissive manner, but that the IL-3 receptor does not directly couple to a PT substrate G protein.

Biological Transport↗

PubMed1991

[Stem cells, clonality and leukemia].

The data we review suggest newer concepts regarding the biology of leukemia. First, all leukemias may originate in a multipotent stem cells. Second, leukemia phenotype may reflect where the leukemia clone expands rather than the site of transformation. Third, preleukemia may always antedate leukemia. And finally, remission and cure may result from re-establishing preleukemia rather than eradicating leukemia cells of favoring their maturation. Also, leukemia and at least some cases of aplastic anemia may represent different ends of a spectrum of one disease.

Clone Cells↗

PubMed1992

Fluctuations in serum cytokine levels in the patient with cyclic neutropenia.

The fluctuations of the levels of serum cytokines in a patient with cyclic neutropenia were studied. The greatest fluctuation was found in granulocyte colony-stimulating factor (G-CSF). Tumor necrosis factor-alpha level fluctuated inversely with fluctuation of G-CSF, and oscillation of interleukin (IL)-6 level preceded that in G-CSF level. It is likely that the variations of the levels of cytokines play a significant role in regulating hematopoiesis in cyclic neutropenia. Our results suggested that the stage of the granulocyte-committed stem cell is the major step of the defect, and the defect at the stage of the multipotent stem cell or bone marrow microenvironment was also suggested.

Adult↗

PubMed1993

At day 8-8.5 of mouse development the yolk sac, not the embryo proper, has lymphoid precursor potential in vivo and in vitro.

We have studied both in vitro and in vivo the formation of lymphocyte progenitors before blood circulation (day 9 of gestation) has started in the mouse embryo, and we have determined the tissue where this occurs. The results demonstrate that the yolk sac of embryos at day 8 and day 8.5 of gestation contains precursor cells that can give rise, in vivo and in vitro, to mature T and B lymphocytes. No lymphoid precursors were found in the embryo proper at this stage of mouse development. The yolk sac cells with lymphocyte precursor potential are most likely multipotent stem cells rather than cell-lineage-determined T- and/or B-lymphocyte progenitors. The defined in vitro assays described here that support differentiation of yolk sac stem cells along the T- or B-lymphocyte pathways also may now facilitate the study of the molecular events leading to cell-lineage commitment of lymphocyte progenitors in the mouse embryo.

Animals↗

PubMed2006

The proximal promoter region of mTert is sufficient to regulate telomerase activity in ES cells and transgenic animals.

BACKGROUND: The reverse transcriptase of telomerase (Tert) controls telomerase activity maintaining the end of linear chromosomes in eukaryotic cells. Telomerase function is highly active in undifferentiated multipotent stem cells, decreases with cell differentiation and is generally absent from most somatic cells in the adult. Its absence is responsible of telomeres shortening in such somatic cells. Using an in vivo transgenic model and an in vitro culture differentiation of adult stem cells, we examined the elements of the mouse Tert (mTert) promoter that control telomerase activity. RESULTS: Three constructs comprising 1, 2 or 5 kb of the mTert promoter sequence coupled to the coding sequence of the green fluorescent protein (EGFP) were electroporated into embryonic stem (ES) cells. Transformed ES cells were able to mimic the expected mTert expression, which was associated to green fluorescence. One and 5 kb promoter produced the higher expression of EGFP, on ES cells. When ES cells were allowed to differentiate to embryoid bodies and to other cell types, they lost gradually the expression of mTert-EGFP as consequence of differentiation. No differences were found among the three constructs analyzed. We then generated transgenic mice with the three constructs. Expression of the reporter gene was monitored by reverse transcription-PCR analysis and EGFP visualization. The mRNA expression of the three constructs was lower than the endogenous mTert, but mimicked the endogenous mTert transcription pattern; however, no fluorescent expression of EGFP was detected in adult tissues. EGFP expression of the three constructs was visualized at the blastocysts stage and in new ES cells generated from them; in the germinal ring of E13 dpc foetuses; in ES-like colonies and in germinal stem cells generated from neonatal and adult testis cells; and in neuroesferes generated from E14 dpc foetuses' brain cells. CONCLUSION: The 1 kb promoter upstream of the initiating ATG codon of mTert contains all the regulatory elements to control telomerase expression in ES cells during in vitro loss of pluripotency. The transgenic mouse lines generated represent an appropriate system to analyze the expression of mouse Tert gene under physiological condition and during establishment of stem cell lines generated from embryonic or adult tissues.

Animals↗

PubMed2006

Signaling events during male germ cell differentiation: update, 2006.

The intracellular transduction of exogenous and cell-autonomous stimuli triggers the transformation of a multipotent stem cell, the spermatogonion, into a highly differentiated, motile and fertile cell, the spermatozoon. This differentiation process is mediated by cell-cell contact and via key players including hormones, growth factors, and cytokines. Female hormones, estrogens and progestins, play a role in the production and functionality of spermatozoon. New findings, however, reconsider the direct action for estrogens on male germ cells while progestins work through non-canonical receptors. Similarly, testosterone, the male hormone, besides acting through its receptor expressed in the somatic cells of testis, seems to work by means of non-classical mechanisms. The recent identification of growth factors, transcriptional regulators, and media for in vitro growth of spermatogonial stem cells should now make it feasible to unravel the entire spermatogenic process. A peculiar feature of the meiotic cycle is the maintenance of condensed chromatin so that DNA duplication is prevented and reduction of genome is achieved. Recently, molecular mechanisms that lead to such a condensation have been discovered. Junctional intercellular complexes between Sertoli and germ cells are critical for coordinating spermatogenesis. Molecular players involved in such cell-cell communication have been identified in Sertoli cells. Now, there is also a need for unravelling the germ cell molecules involved. These issues are the major topics which are discussed here with the goal to suggest a possible answer.

Cell Differentiation↗

PubMedDate not supplied

Expression of the hybrid P210 bcr/abl protein in Philadelphia chromosome positive B-lymphoid cell lines.

An altered c-abl protein (P210) bearing increased tyrosine kinase activity represents the product of the hybrid bcr/c-abl gene arising as a consequence of the Philadelphia (Ph1) chromosome translocation, the consistent cytogenetic abnormality of chronic myelogenous leukemia (CML). Although the chronic phase of this disease is substantially characterized by a marked proliferation of myeloid cells, the Ph1 translocation occurs in an early multipotent stem cell, giving rise to both myeloid and lymphoid cell lineages. Here we show that P210 bcr/abl protein expression varies greatly in different Ph1 chromosome positive B-lymphoid cell lines obtained from Epstein-Barr virus-transformed lymphocytes of a CML patient in the chronic phase. In addition Ph1 positive and Ph1 negative lymphoid cell lines obtained from the same patient were tested for a number of biological properties including the immunophenotype, the capacity to grow in soft agar and possible tumorigenicity in nude mice. No differences were found.

Animals↗

PubMedDate not supplied

Clonality study by fluorescence in situ hybridization of a patient with refractory anemia with ringed sideroblasts and monosomy 7.

Myelodysplastic syndromes (MDS) are stem cell diseases but it is still controversial whether chromosomal abnormalities occurring in these disorders affect a multipotent stem cell or a committed progenitor. We studied a case of refractory anemia with ringed sideroblasts (RARS) and monosomy 7 in 100% of examined metaphases. Using the fluorescence in situ hybridization (FISH) technique with a probe specific for the centromeric region of chromosome 7, we demonstrated that 15% of BM cells fixed in acetic acid/methanol exhibited a normal diploid karyotype. Applying the FISH technique on PB cells smeared onto a slide, we observed that lymphocytes maintain two chromosomes 7, whereas other leukocytes exhibited monosomy 7. Our study confirms that chromosomal abnormalities found in MDS can occur in cells capable of differentiation along granulocytic and monocytic lineages, but not along the lymphocytic lineage.

Anemia, Sideroblastic↗

PubMed1993

Synergistic interactions in haemopoiesis: biological implications and clinical use.

Growth factors promote the survival and proliferation of haemopoietic stem and progenitor cells, and in their absence the haemopoietic cells undergo apoptosis and die. The results of studies reported here indicate that multipotent stem cells have receptors for most, if not all, of the growth factors, but that even saturated binding of the receptors for a single growth factor is not sufficient to transduce an effective stimulus for the proliferation of these cells (possibly due to very low receptor numbers). However, when the growth factors are combined synergistic effects can be seen. Studies in which stem cell factor was used in combination with other growth factors showed that stem cell factor allowed the survival of stem cells, while a second growth factor (granulocyte-macrophage colony-stimulating factor) stimulated the stem cells to develop normally. Stem cell factor was also shown to alter the dose-response relationships of developing haemopoietic cells for other growth factors.

Bone Marrow Cells↗

PubMed1984

Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin.

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.

Acute Disease↗

PubMed2004

Pax genes in myogenesis: alternate transcripts add complexity.

Pax3 and Pax7 are powerful myogenic inducers and hence play a critical role in skeletal muscle development and regeneration. In this paper we discuss the role of Pax3 and Pax7 in dorsal patterning of the somite with subsequent determination of myogenic precursor cells for muscle formation within the developing embryo and in adult muscle. Recent evidence of the ability of stem cells to contribute to muscle regeneration in adult tissues, and the role of Pax7 in conversion of multipotent stem cells to the myogenic lineage are also discussed. Several tissue specific Pax7 transcripts that encode isoforms with different DNA binding characteristics and potentially distinct transactivation specificities are identified. The expression of a range of transcripts in the determination of different tissue lineages and distinct cell populations both in the embryo and in the adult indicates an extraordinary level of complexity. A detailed understanding of these molecules and their functions during embryogenesis and adult muscle formation is imperative for future stem cell therapies.

Alternative Splicing↗

PubMed2001

Context-dependent regulation of fate decisions in multipotent progenitor cells of the peripheral nervous system.

A challenging problem in neural crest development is to understand how a migratory population of multipotent stem cells gives rise to a diverse array of differentiated cell types in the correct spatiotemporal manner. There is now ample evidence that this process involves the generation of postmigratory progenitor cells present in a variety of neural crest targets. When individual progenitors are challenged by instructive growth factors they are able to produce neural and non-neural cells, raising the question of how fate restrictions appropriate to a given embryonic location are regulated in multipotent postmigratory progenitor cells. Although some of the extracellular cues involved have been identified, it is likely that fate decisions in progenitor cells are controlled by the combinatorial action of multiple environmental signals. Moreover, cell type specificity is thought to be regulated by an interplay between extracellular and intracellular cues. We are just beginning to unravel some of the mechanisms that allow the context-dependent integration of cell-extrinsic and cell-intrinsic signals in multipotent progenitor cells.

Animals↗

PubMed2005

In vivo bone formation by human marrow stromal cells in biodegradable scaffolds that release dexamethasone and ascorbate-2-phosphate.

An unsolved problem with stem cell-based engineering of bone tissue is how to provide a microenvironment that promotes the osteogenic differentiation of multipotent stem cells. Previously, we fabricated porous poly(D,L-lactide-co-glycolide) (PLGA) scaffolds that released biologically active dexamethasone (Dex) and ascorbate-2-phosphate (AsP), and that acted as osteogenic scaffolds. To determine whether these osteogenic scaffolds can be used for bone formation in vivo, we seeded multipotent human marrow stromal cells (hMSCs) onto the scaffolds and implanted them subcutaneously into athymic mice. Higher alkaline phosphatase expression was observed in hMSCs in the osteogenic scaffolds compared with that of hMSCs in control scaffolds. Furthermore, there was more calcium deposition and stronger von Kossa staining in the osteogenic scaffolds, which suggested that there was enhanced mineralized bone formation. We failed to detect cartilage in the osteogenic scaffolds (negative Safranin O staining), which implied that there was intramembranous ossification. This is the first study to demonstrate the successful formation of mineralized bone tissue in vivo by hMSCs in PLGA scaffolds that release Dex and AsP.

Alkaline Phosphatase↗

PubMed2006

Cardiac regeneration.

The role and even the existence of new myocyte formation in the adult heart remain controversial. Documentation of cell cycle regulators, deoxyribonucleic acid synthesis, and mitotic images has only in part modified the view that myocardial growth can be accomplished exclusively from hypertrophy of an irreplaceable population of differentiated myocytes. However, myocyte regeneration and death occur physiologically, and these cellular processes are enhanced in pathologic states. These observations have challenged the view of the heart as a postmitotic organ and have proposed a new paradigm in which parenchymal and non-parenchymal cells are continuously replaced by newly formed younger populations of myocytes as well as by vascular smooth muscle and endothelial cells. Heart homeostasis is regulated by a stem cell compartment characterized by multipotent cardiac stem cells that possess the ability to acquire the distinct cell lineages of the myocardium. Similarly, adult bone marrow cells are able to differentiate into cells beyond their own tissue boundary and create cardiomyocytes and coronary vessels. This process has been termed developmental plasticity or transdifferentiation. Because of these properties, bone marrow cells and cardiac stem cells have been employed experimentally in the reconstitution of dead myocardium after infarction. These cell classes hold promise for the treatment of heart failure in humans.

Animals↗