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PubMed1995

Stimulation of fetal hemoglobin production by short chain fatty acids.

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.

Adult↗
PubMed1995

Blood volume and erythropoiesis in the rat during spaceflight.

A decreased red blood cell mass (RBCM) and plasma volume (PV) have been consistently found in humans after return from spaceflight. Rats flown on the Spacelab Life Sciences-1 mission were studied to assess changes in RBCM, PV, erythropoiesis, and iron economy. The RBCM and PV increased in both ground control and flight animals as expected for growing rats. However on landing day, both the RBCM and PV, when normalized for body mass, were significantly decreased in the spaceflight animals. During an 8-d postflight observation period, iron incorporation into circulating red blood cells was diminished in the flight animals. During the first 4 d postflight, increases in reticulocyte counts were significantly smaller in the flight than the control animals. Fewer erythropoietin-responsive progenitor cells were recovered from the bone marrow of flight animals after landing than control rats. Serum erythropoietin (EPO) levels were the same in both groups. Thus, rats subjected to a 9-d spaceflight had less increase in RBCM than controls and diminished erythropoiesis during an 8-d post-spaceflight observation period. The rat, like humans, appears to require a smaller blood volume in microgravity.

Animals↗
PubMed1993

Antipeptide antibodies as probes of the recombinant and endogenous murine erythropoietin receptors.

The binding of erythropoietin (Epo) to its plasma membrane receptor activates signal pathways that result in erythroid cell proliferation and differentiation. To elucidate the structural features of the receptor that are important for hormone binding and signaling, we have developed a series of site-specific antibody probes. These antibodies were raised against synthetic peptides homologous to six exoplasmic domains and one cytoplasmic domain of the murine receptor and were affinity-purified by binding to their respective peptide antigen, immobilized on agarose. Western blot analyses demonstrated that the recombinant receptor expressed transiently in COS-7 cells is synthesized as three protein species of 62, 64, and 66 kd, consistent with previous observations. Importantly, probing the endogenous receptor in both virally transformed erythroleukemia cells and normal erythroid cells demonstrated similar 62- to 66-kd receptor species. The affinity-purified antibodies also recognized several antigenically related proteins. An examination of the capacity of the antireceptor antibodies to block receptor activation by Epo revealed that antibodies to five of the six exoplasmic domains blocked the receptor. This was reversed with excess Epo. Inhibition of receptor activation by antibody probes to five discrete hydrophilic domains suggests that receptor function may be critically dependent on the structural integrity (conformation) of the entire exoplasmic portion.

Amino Acid Sequence↗
PubMed1994

Expression of sialosyl-Tn in colony-forming unit-erythroid, erythroblasts, B cells, and a subset of CD4+ cells.

The epitopes Tn and sialosyl-Tn are expressed on erythrocytes of individuals with a very rare blood group, who often suffer from "Tn syndrome." We surveyed expression of Tn and sialosyl-Tn in normal blood cells, malignant transformed cells, and progenitor stem cells from bone marrow (BM). An anti-Tn antibody, IE3, and an anti-sialosyl-Tn antibody, TKH2, were used in this study. TKH2 reacted with erythroblasts, B cells, and a subset of CD4+ cells; but not with erythrocytes. Erythroblastic cell lines (K562, HEL, and UT7/EPO) and B-cell lines (Daudi, Raji, and B-cell lines transformed by Epstein-Barr virus) showed reactivity to TKH2. Similar results from the reactivity of TKH2 with transformed cells from leukemia patients and lymphoma patients were obtained; TKH2 reacted with blasts from erythroleukemia (M6; for 4 of 4 cases) and with lymphocytes from B-cell chronic lymphocytic leukemia (3 of 3), B-cell lymphoma (5 of 5), and CD4+ adult T-cell leukemia (4 of 4), but did not react with blasts from acute myeloid leukemia (M0 to M5; 0 of 22) or acute lymphoid leukemia (B-lymphoid leukemia, 0 of 11; T-lymphoid leukemia, 0 of 2; undifferentiated leukemia, 0 of 1). IE3 did not react with all of the tested cells. CD2-CD19-TKH2+ normal BM cells (BMC) contained blasts and various maturation stages of erythroblasts. The TKH2+ cells produced a large number of colony-forming unit-erythroid (CFU-E) colonies, whereas they produced a small number of burst-forming unit-erythroid colonies and CFU-granulocyte-macrophage colonies. CD34+ normal BMC did not express Tn and sialosyl-Tn. These findings suggest that sialosyl-Tn expresses in CFU-E to erythroblasts.

Antibodies, Monoclonal↗
PubMed1993

[Significance of sympathetic-adrenal structures in hematopoiesis regulation in cytostatic myelodepression].

The role of the sympathetic nervous system in the regulation of bone marrow hematopoiesis has been studied on mice CBA after administration of 5-fluorouracil (114 mg/kg). The double injection (3-5 minutes before and 5 hours after 5 + U) of ganglionic blocking drug (pentamine, 6 mg/kg), alpha-adrenergic (dihydroergotamine, 3.9 mg/kg) or beta-adrenergic antagonists (propranolol, 5 mg/kg) inhibited the post-cytostatic reparation of erythro- and granulocytopoiesis. Besides, addition of the same neurotropic antagonists and 5-FU (10(-7) M) to bone marrow culture led to 1.5-3 fold decrease of cell content in comparison with alone cytostatic after 24 hours incubation. On the contrary injection of neuroblocking agents (twice in 5 hours) on day 3 after 5-FU administration elevated the total count of erythroid cells immature and mature granulocytic leukocytes in bone marrow and polymorphonuclear leukocytes in blood. Thus, the unequal role of the sympathetic nervous system in the regulation of hematopoiesis at the different periods after high dose of 5-FU administration has been demonstrated.

Adrenal Glands↗
PubMed1994

Oncogenes and erythroid differentiation.

Committed erythroid progenitors are the cellular targets of oncogene-carrying avian and murine retroviruses that induce acute erythroleukemia. Normally, these cells undergo a fixed program of 5-10 cell divisions while terminally differentiating into erythrocytes. The sustained self-renewal observed in the context of their retrovirus-mediated leukemic transformation has been viewed as an abnormal, oncogene-induced effect. Recently, however, it was found that certain combinations of growth/differentiation hormones (e.g. TGF-alpha and estradiol) can induce normal avian erythroid progenitors to undergo a similarly extensive self-renewal as caused by oncogenes. This leads to the hypothesis that leukemia-inducing oncogenes take advantage of the committed erythroid progenitors' capacity for self-renewal rather than reprogramming their targets to abnormal growth, as suspected previously. These findings and their implications will be discussed.

Animals↗
PubMed1993

Transient and permanent engraftment potential of murine hematopoietic stem cell subsets: differential effects of host conditioning with gamma radiation and cytotoxic drugs.

Transplant of sorted donor (B6-Gpi-1a) hematopoietic stem cell subsets and host (B6-Gpi-1b) treatment with total body irradiation (TBI) or cytotoxic drugs were compared for induction of short- and long-term engraftment in a murine chimera model of congenic bone marrow transplantation (BMT). Parallel studies on donor and host marrow were performed in vitro in long-term bone marrow cultures to determine early and late cobblestone area forming cell (CAFC) frequencies in the grafts or in the transplant recipients 1 day after conditioning. Bone marrow cells (BMC) sorted for high wheat germ agglutinin affinity (WGA ) were enriched about 30-fold for early developing CAFC (colony-forming unit-spleen [CFU-S]) but not for primitive late CAFC (pre-CFU-S). This fraction showed only temporary engraftment when transplanted in irradiated recipients. In contrast, the low affinity (WGA+) fraction were preferentially enriched (200- to 300-fold) for late developing CAFC and were very effective for providing stable long-term engraftment following transplantation. Substituting radiation for chemotherapy in the host conditioning treatment also had diverse effects on the development of bone marrow engraftment. Pretreatment with 5-fluorouracil (5-FU, 200 mg/kg) allowed a discrete wave of donor engraftment that peaked at 2 to 4 weeks and then subsided to leave mostly host cells at 10 weeks and beyond. Busulfan preparation gave over 50% engraftment at 1 month after BMT but this continued to increase to reach stable donor chimerism of 80 to 90% beyond 10 weeks. The level of long-term engraftment given by 50 mg/kg busulfan appeared similar to that induced by doses of 6 to 8 Gy TBI. The changing patterns of erythroid chimerism for each preparative agent showed a remarkable correlation with depletion of defined hematopoietic stem cell subsets as quantified using the CAFC assay at 1 day after recipient treatment. These findings collectively show that the level of depletion of host CFU-S (CAFC-10) determines the extent of early and transient repopulation, whereas the degree of pre-CFU-S (CAFC-35) depletion determines the percentage of stable chimerism. Preliminary data on bone marrow CAFC content at 9 months after busulfan and BMT revealed a long-term reduction of the stem cell pool by about 50% but with relatively minor effects on supporting bone marrow stromas. The differential cytotoxic effects on stem cell subsets in relation to subsequent donor marrow engraftment offer a systematic and mechanistic approach toward identifying more effective chemotherapeutic compounds for use in clinical BMT conditioning regimens.

Animals↗
PubMed1994

Modulation of hematopoiesis by lymphocyte membrane-derived components.

Membrane bound erythroid burst-promoting activity (mBPA) is an integral membrane protein that is present on normal B-cells and some activated T-cells, that induces burst-forming units-erythroid (BFU-E) when cultured with human erythropoietin (rHuEpo). Plasma membranes and vesicles shed from the leukemic A-1 cell line express mBPA. This activity derived from both A-1 cells and normal B-cells can be immunoadsorbed by the D3A4 antibody raised against mBPA. In this study, we demonstrate that interferon-gamma (IFN-gamma) suppresses BFU-E proliferation when added directly to culture of normal human bone marrow cells and in the absence and presence of A-1 cells. However, FACS analysis reveals that IFN-gamma enhances the surface expression of mBPA on A-1 cells. The role of IFN-gamma in modulating erythropoiesis in vitro is discussed with respect to the role of shedding membrane-derived vesicles from the B-cell surface.

Cells, Cultured↗
PubMed1993

Correlation of in vitro enhancement of erythropoiesis and clinical response to steroids in Diamond-Blackfan anaemia.

To investigate whether the clinical response to steroids in Diamond-Blackfan anaemia (DBA) can be predicted in vitro, erythroid cultures from six patients was performed. The increment of burst forming unit erythroid (BFU-E) and colony forming unit erythroid (CFU-E) derived colonies had been studied with the in vitro addition of steroids. Our results showed: 1) a relative insensitivity to low and optimum concentration of erythropoietin (Epo) in cultures, and 2) lower CFU-E and BFU-E colony formation in all cases studied. (CFU-Es of normal controls/10(5) cells; were 85.6, BFU-Es 37.8, while the patients' CFU-E were 18.1 and BFU-E 7/10(5) cells with two IU of Epo) with poor or no growth in three cases, 3) increment up to 60-110% with in vitro addition of steroids in three cases, 4) high serum Epo levels in all Diamond-Blackfan anaemia patients, and 5) clinical response to steroids in the three patients who responded in vitro.

Adult↗
PubMed1996

The synthetic tetrapeptide AcSDKP protects cells that reconstitute long-term bone marrow stromal cultures from the effects of mafosfamide (Asta Z 7654).

The tetrapeptide AcSDKP (Seraspenide) has been described as an inhibitor of CFU-S entry into DNA synthesis; as a result, its administration can protect mice against lethal doses of cytosine arabinoside. We have studied the ability of AcSDKP to protect and promote the growth of early CD34+ human bone marrow (BM) stem cells in Dexter long-term cultures following exposure to a toxic concentration of mafosfamide. The protection assay was based on the preincubation of CD34+ BM cells with or without AcSDKP at 10(-10)M or 10(-8)M followed by exposure to a toxic dose of mafosfamide (100 micrograms/mL). The production of granulomonocytic progenitor cells (CFU-GM) was subsequently studied in long-term bone marrow cultures (LTBMC) of the samples exposed to mafosfamide and preincubated or not (control) with AcSDKP. After a lag of 2 to 3 weeks, the number of CFU-GM peaked at the 4th to 5th week in both the supernatant and the adherent layers. A greater production of granulomonocytic progenitor cells was observed in LTBMC from the samples preincubated with AcSDKP compared with control cells. Depending on the BM samples, enhanced production of CFU-GM in the AcSDKP-treated cell cultures was observed at either the 10(-10)M or 10(-8)M concentration. These results suggest that AcSDKP can protect in vitro human long-term culture-initiating cells (LTC-IC) from mafosfamide, resulting in an increased production of CFU-GM from this early stem cell compartment.

Amino Acid Sequence↗
PubMed1995

Murine splenic proliferative response to human recombinant erythropoietin along hypoxia.

Hypoxia is the best physiological stress to disturb the erythropoietic steady state. The present study has been undertaken in the aim to analize the splenic erythropoietic proliferative response with different doses of recombinant human erythropoietin under hypoxic conditions along 18 days using the DNA synthesis assay. Normoxic splenic progenitors failed to show significative erythroid replication at 0 days. A clearly rh Epo response was noticed from 2 to 8 days of hypoxia. Splenic proliferation returned to basal pattern from 10 days to the end of the experience. The highest proliferative activity, 25 fold increase over control (p < 0.001), was found at 6 days from 62.5 to 250 mU/ml rh Epo. These results support suggestions that hypoxia induces a transiently erythroid splenic proliferative response changing its quantitative parameters in the Epo dose-response relationship during the physiological adaptation.

Animals↗
PubMed1996

Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow.

The aim of the present study was to determine if the human erythroid (E) and megakaryocytic (MK) lineages were closely linked to the existence of a bipotent burst-forming unit (BFU) E/MK progenitor. In methylcellulose cultures, BFU-E/MK colonies were observed at day 12 and closely resembled mature BFU-E with the exception that the erythroid component was surrounded by MK. These colonies were quite different from the colony forming unit (CFU)-GEMM-derived colonies, which were composed of a larger number of erythroblasts and which developed later in culture. The existence of these bilineage colonies composed of 100 to 1,000 erythroblasts intermingled with a few MK and without granulocytic cells was confirmed by the plasma clot technique and immunoalkaline phosphatase labeling of the MK. To investigate if this bipotent progenitor belonged to the compartment of primitive progenitors, CD34+ marrow cells were subfractionated according to expression of the CD38 antigen. The bipotent BFU-E/MK progenitor as well as a large fraction of MK progenitors were found in the CD34+ CD38+/- or in the CD34+ CD38- cell fractions. Growth of this bipotent BFU-E/MK progenitor required the combination of stem cell factor (SCF), Interleukin-3 (IL-3), and Epo in serum free conditions. Addition of IL-6 had only a marginal effect, whereas megakaryocyte growth and development factor (MGDF) was not an absolute requirement, but slightly increased the plating efficiency of CFU-MK and of BFU-E/MK progenitors when combined with SCF, IL-3, and Epo. In contrast, when these cultures were performed in the presence of 30% fetal calf serum, no BFU-E/MK colonies were observed irrespective of the combination of growth factors used, including the presence of MGDF; however, inclusion of the MS-5 cell line restored the growth of this bipotent progenitor. In contrast, in cultures performed in the presence of human normal or aplastic plasma, MS-5 had only a slight effect on the cloning efficiency but improved MK cytoplasmic maturation and MK size, suggesting that the main effect of MS-5 is to diminish the inhibitory effect of the fetal calf serum on the MK differentiation. The clonal origin of bipotent BFU-E/MK colonies was demonstrated in liquid culture of single CD34+ CD38low cells by immunophenotyping individual clones. At day 12, 30% of the clones contained erythroblasts (glycophorin A+) and some MK (CD41+) without granulocytes (G) or macrophages (M) (CD14+ and CD15+). At day 20, clones containing erythroblasts and MK were rare (5%). In contrast multilineage clones could be frequently detected at this time without passage from BFU-E/MK clones at day 12 to GEMM at day 20. These results suggest that a bipotent BFU-E/MK progenitor may be a nonrandom step in the hierarchical development of stem cells.

ADP-ribosyl Cyclase↗
PubMed1996

Low levels of erythroid and myeloid progenitors in thrombopoietin-and c-mpl-deficient mice.

Thrombopoietin (TPO), the ligand for the c-mpl receptor, has been shown to be the major regulator of platelet production. Mice deficient in either c-mpl or TPO generated by homologous recombination show a dramatic decrease in platelet counts, but other blood cell counts are normal. Because TPO treatment of myelosuppressed mice not only enhances the recovery of platelets but also accelerates erythroid recovery, we investigated the levels of myeloid and erythroid progenitor cells in TPO-or c-mpl-deficient mice. Our results show that the number of megakaryocyte, granulocyte-macrophage, erythroid, and multilineage progenitors are significantly reduced in the bone marrow, spleen, and peripheral blood of either TPO-or c-mpl-deficient mice. Administration of recombinant murine TPO to TPO-deficient mice and control littermate mice significantly increased the absolute number of myeloid, erythroid, and mixed progenitors in bone marrow and spleen. This increase was especially apparent in TPO-deficient mice where numbers were increased to a level greater than in diluent-treated control mice and approached or equaled that in the TPO-treated control mice. Moreover, TPO-administration greatly increased the number of circulating progenitors as well as platelets in both TPO-deficient and control mice. Furthermore, the megakaryocytopoietic activity of other cytokines in the absence of a functional TPO or c-mpl gene was shown both in vitro and in vivo.

Animals↗
PubMed1996

[Cytokines regulate apoptosis of leukemic cells].

It is clear that cytokines regulate normal hematopoiesis including proliferation, differentiation, and apoptosis (programmed cell death). Leukemia is a disorder of unbalance between excessive proliferation and inappropriate apoptosis. Leukemic cells are also stimulated by cytokines similar to normal hematopoietic cells. It is reported that the oncogenes and tumor suppressor genes are associated with not only leukemogenesis but also cell cycle, for example proliferation, differentiation, and apoptosis (programmed cell death). We found that G-CSF leads to apoptosis of radiation induced murine leukemia cell line (C2M-A5), and its apoptosis is dependent on cell cycle. From these results together with other related reports, cytokines seem to be a key substance of apoptosis of leukemic cells and the apoptosis inducing therapy will be a new strategy for leukemia therapy.

Animals↗
PubMedDate not supplied

Recovery and characterization of CD34+ cord blood cells after cryopreservation.

Hematopoietic stem and progenitor cell transplantation is an important therapy for certain hematological and malignant disorders, and these cells are being used as vehicles for potential gene therapy approaches to treatment. Umbilical cord blood is a rich source of stem and progenitor cells, which can be efficiently transduced by viral vectors with new genetic material, and these cells have been used in both allogeneic and autologous transplant settings, the latter setting used by others for gene transfer as a possible means of gene therapy. Since cord blood banking is increasingly being considered as an adjunct for allogeneic and autologous transplantation, the present studies were done in order to evaluate the consequences of cryopreserving highly purified CD34+ cells from cord blood. The results demonstrate that CD34+ cord blood cells can be frozen in cryopreserved form and recovered efficiently with cell cycle, proliferative and cell expansion characteristics equivalent to the pre-freeze samples of cells. This information complements previous studies from our group demonstrating the efficient freezing of relatively unseparated populations of cord blood cells, and should be of practical use for future studies involving banking and use of cord blood stem and progenitor cells.

Antigens, CD34↗
PubMed1997

Ability of early acting cytokines to directly promote survival and suppress apoptosis of human primitive CD34+CD38- bone marrow cells with multilineage potential at the single-cell level: key role of thrombopoietin.

Purified primitive progenitor/stem cells from bone marrow represent likely target populations for ex vivo expansion of stem cells to be used in high-dose chemotherapy or gene therapy. Whereas such primitive progenitor cells require combined stimulation by multiple cytokines for growth, some cytokines selectively promote viability rather than growth when acting individually. We investigated here for the first time the direct effects of cytokines on survival of primitive CD34+CD38- human bone marrow progenitor cells at the single-cell level. Interleukin-3 (IL-3) and the ligands for c-kit (KL) and flt3 (FL) had direct and selective viability-promoting effects on a small fraction of CD34+CD38- but not CD34+CD38+ progenitor cells. Interestingly, the recently cloned thrombopoietin (Tpo), although stimulating little growth, kept most CD34+CD38- progenitors viable after prolonged culture, maintaining twofold and fourfold more progenitors viable than KL and IL-3, respectively. A high fraction of these progenitors had a combined myeloid and erythroid differentiation potential, as well as capacity for prolonged production of progenitor cells under stroma-independent conditions. In addition, Tpo promoted viability of CD34+CD38- long-term culture-initiating cells, further supporting the idea that Tpo promotes viability of primitive human progenitor cells. Finally, Tpo suppressed apoptosis of CD34+CD38- cells in culture. Thus, the present studies show a novel effect of Tpo, implicating a potential role of this cytokine in maintaining quiescent primitive human progenitor cells viable.

ADP-ribosyl Cyclase↗