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PubMed1993

Expression of functional human CSF-1 receptors on mouse bone marrow erythroid progenitor cells.

We have previously shown that a murine multipotent hematopoietic cell line could proliferate in response to CSF-1 after retroviral transfer of human CSF-1 receptor (CSF-1R) gene (c-fms) without loss of the erythroid differentiation potential. In the light of these data, we asked whether ectopic expression of human c-fms gene would lead to the conditional immortalization of murine hematopoietic progenitor cells. In the present studies, murine bone marrow cells were infected with recombinant retroviruses containing the human c-fms cDNA. We found that CSF-1 could exert a stimulatory activity on erythroid progenitors in the presence of Epo only when bone marrow cells had been previously infected with c-fms retroviruses. In addition, expression of human CSF-1R in murine Epo-dependent, v-src-immortalized cells resulted in CSF-1-dependent proliferation of these cells in the absence of Epo. These data show that human CSF-1R (i) can stimulate early bone marrow erythroid progenitors, (ii) might require additional signals provided by oncogenes or cytokine receptors to transduce a mitogenic signal into mouse bone marrow erythroid progenitors.

Animals↗
PubMed1994

Expression and extracellular release of transferrin receptors during peripheral erythroid progenitor cell differentiation in liquid culture.

The expression and extracellular release of transferrin receptor (TR) was investigated by in vitro model system of erythroid differentiation. Human peripheral blood mononuclear cells were cultured with interleukin-3 (IL-3) for 7 days, and with erythropoietin (EPO) for an additional 8 days. After EPO stimulation, IL-3-stimulated blastic cells were serially differentiated into mature erythrocytes. [3H]-thymidine incorporation of cultured cells increased linearly from day 0 to 5, followed by a decrease. Flow cytometric analysis showed an increase of TR expression from day 0 to 5, followed by a slight decrease. By metabolic labeling with [35S]methionine and immunoprecipitation, the cell lysate exhibited a 95-kD band corresponding to the intact TR on sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography at day 5, when polychromatic erythroblasts had their peak. The culture supernatant solubilized by tween-20 exhibited a 95-kD and an 85-kD band on days 5 and 8, which corresponded to the intact and the truncated forms of TR, respectively. The 95-kD band was more intense at day 5 than at day 8. The reverse transcriptase-polymerase chain reaction assay showed that the receptor-mRNA expression was parallel to receptor synthesis. Thus, the synthesis and expression of TR on erythrocytes is associated mainly with cell proliferation in the early phase, and with both cell proliferation and hemoglobin production in the middle to late phases of maturation. Concomitantly, the extracellular release of TR from erythrocytes occurs in the middle to late phases of maturation. These data suggest that polychromatic erythroblasts release soluble TR as both intact and truncated forms and may be an important source of serum TR implicated as an index for erythropoietic activity in the marrow.

Cell Differentiation↗
PubMed1994

Basic fibroblast growth factor antagonizes transforming growth factor beta-mediated erythroid differentiation in K562 cells.

Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF is a hematopoietic cytokine that acts on progenitor cells in concert with other cytokines to promote their proliferation. TGF-beta induces erythroid differentiation in K562 cells. To determine whether bFGF might act on progenitor cells by antagonizing the effects of cytokines that induce differentiation, we determined the effects of bFGF on the TGF-beta-mediated induction of hemoglobin synthesis in K562 cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. bFGF was most effective at antagonizing the TGF-beta-mediated induction of hemoglobin if it and TGF-beta were added simultaneously to K562 cells, but delayed addition of bFGF to TGF-beta-treated cultures still resulted in significant inhibition of hemoglobin synthesis. The inhibitory effects of bFGF on hemoglobin production were fully reversible, showing that bFGF did not permanently alter the phenotype of K562 cells. The hemin-mediated induction of hemoglobin synthesis in K562 cells was only partially negated by bFGF. bFGF also diminished the expression of glycophorin A on the surface of K562 cells. These results indicate that bFGF might increase progenitor/stem cell numbers by antagonizing the effects of cytokines that induce differentiation, thereby increasing the pool of proliferating progenitor/stem cells.

Cell Differentiation↗
PubMed1993

[Changes in the population composition and the rates of proliferation and specialization of erythroid cells in rats with experimental anemia].

Cytomorphologic, morphometric and population analyses have revealed that during acute anemia, induced by phenylhydrazin, the proliferative activity of erythroblasts increases, an abrupt change in the structures of erythroid populations of both bone marrow and peripheral blood is observed, together with the increase in the rates of their specialization. Also, the ratio of the stem cells which differentiate by the erythroid pathway is increased, and the macro- and microcytosis mechanisms, which are essentially salient in normal conditions, are switched on. The roles of macro- and microcytes in the restoration of the normal amount of erythroid cells and haemoglobin contents in the blood are discussed.

Acute Disease↗
PubMed1993

Long-term effects of recombinant human erythropoietin on bone marrow progenitor cells.

Eleven uraemic patients were treated with recombinant human erythropoietin (rHuEpo). Seven haemodialysis patients and four peritoneal dialysis patients received a starting dose of 80 IU/kg i.v. and 40 IU/kg s.c. respectively, thrice weekly. The number of burst-forming-unit erythroid (BFU-E), colony-forming-unit erythroid (CFU-E), granulocyte-monocyte (CFU-GM) and megakaryocyte (CFU-Mk) were assayed 2 weeks before (D0), and 1 (M1) and 6 months (M6) after the initiation of rHuEpo treatment by means of a commonly applied in-vitro clonal assay. All the patients showed the same haematopoietic response. A significant increase of CFU-E and CFU-Mk could be observed within 1 month of treatment. At this time, no significant modification was observed in BFU-E and CFU-GM number. At the 6th month the increase of CFU-E was maintained, whereas a significant fall of BFU-E, CFU-GM and CFU-Mk was observed. These results suggest that in-vivo effects of rHuEpo are not restricted to the erythroid lineage but that erythropoietin might also act as a co-factor of megakaryopoiesis. In the long term erythropoietin might induce erythroid differentiation in multipotent progenitor cells at the expense of the non-erythroid progenitors.

Adult↗
PubMed1993

9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro.

Retinoic acid exhibits effects on the proliferation and differentiation of many hematopoietic cells. Cellular responsiveness to retinoic acid (RA) is conferred through two distinct classes of nuclear receptors, the RA receptors (RARs) and the retinoid X receptors (RXRs). The RARs bind to both 9-cis- and all-trans-RAs, but 9-cis-RA alone directly binds and activates RXR. This suggested that 9-cis-RA could have expanded hematopoietic activities as compared with all-trans-RA. We compared the abilities of 9-cis- and all-trans-RAs to induce differentiation and inhibit proliferation of three acute myelogenous leukemia (AML) cell lines and fresh leukemic cells from 28 patients and found that: (1) 9-cis-RA in general was more potent than all-trans-RA in suppressing the clonal growth of two AML cell lines and 17 AML samples from patients, including four from individuals with acute promyelocytic leukemia (APL). Eleven leukemic samples, including three from patients with chronic myelogenous or chronic myelomonocytic leukemia, were relatively refractory to both retinoids. (2) The range of activities of both retinoids was similar except that the clonal growth of samples from three AML patients were inhibited by 9-cis-RA, but not by all-trans-RA. (3) Both retinoids inhibited the clonal proliferation of leukemia cells without necessarily inducing their differentiation; in fact, the only fresh AML cells that were able to undergo differentiation were from patients with APL and one individual with M2 AML. (4) Both retinoids enhanced myeloid and erythroid clonal growth from normal individuals, and 9-cis-RA showed slightly more stimulation of the myeloid clonal growth than did the all-trans-RA. Our study suggests that 9-cis-RA is worthy of further study for the treatment of selected individuals with AML.

Cell Differentiation↗
PubMed1993

Activin A suppresses proliferation of interleukin-3-responsive granulocyte-macrophage colony-forming progenitors and stimulates proliferation and differentiation of interleukin-3-responsive erythroid burst-forming progenitors in the peripheral blood.

We examined the effects of activin A on the proliferation and differentiation of immature hematopoietic progenitors prepared from peripheral blood (PB) using methylcellulose and liquid-suspension culture. In a kinetic analysis, colony formation by PB granulocyte-macrophage colony-forming unit (CFU-GM) was delayed in a dose-dependent manner by the addition of activin A only when stimulated with interleukin-3 (IL-3), but not when stimulated with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or stem cell factor (SCF) plus G-CSF. DNA-synthesizing CFU-GM was increased by IL-3, but this effect was abolished by activin A. In contrast, PB erythroid burst-forming unit (BFU-E) was accelerated by the addition of activin A only when exposed to IL-3 plus erythropoietin (Epo), but not when exposed to Epo or Epo plus SCF. DNA-synthesizing BFU-E was increased by IL-3 and activin A, alone and additively in combination. In a mixed culture of myeloid and erythroid progenitors, activin A increased the numbers of BFU-E and CFU-Mix colonies at concentrations of 1 and 10 ng/mL and decreased the number of CFU-GM colonies in a dose-dependent manner. However, in a liquid-suspension culture of erythroid progenitors, activin A decreased total cell count and the percentage of hemoglobin-containing cells only when cells were exposed to IL-3 plus Epo. These results indicate that activin A suppresses the proliferation of IL-3-responsive CFU-GM progenitors and stimulates the proliferation and differentiation of IL-3-responsive BFU-E progenitors, and suggest that activin A acts as a commitment factor of immature hematopoietic progenitors for erythroid differentiation.

Activins↗
PubMed1996

Erythropoietin-like activity in vivo of the fusion protein rhIL-6/IL-2 (CH925).

CH925 is a novel cytokine of a fusion protein interleukin-6 (IL-6)/IL-2 exhibiting erythropoietin (Epo)-like effects in vivo and ex vivo, in addition to its enhanced effects compared to IL-2 and IL-6 reported by us previously, which indicates its potential clinical use. Our present study was undertaken to determine the Epo-like activity of CH925 in vivo. The reticulocyte response was observed in transfusion-induced polycythemic mice by using flow cytometry with pyronin Y staining. On day 2 after injection of CH925, the average number of reticulocytes was 2.11% in the group given 250 micrograms/kg/d and 1.01% for 100 micrograms/kg/d. The mean fluorescence intensity (MFI) also significantly increased. Longitudinal studies of CH925 were performed on days 2, 4, and 10, and reticulocyte counts increased up to a peak on day 4. Activity of CH925 (100 micrograms/kg/d) corresponds to 1 U of standard rhEpo in our study.

Animals↗
PubMed1996

Retroviral transfer of the recombinant human erythropoietin receptor gene into single hematopoietic stem/progenitor cells from human cord blood increases the number of erythropoietin-dependent erythroid colonies.

To test whether an enforced expression of a lineage-specific cytokine receptor would influence the proliferation/differentiation of hematopoietic stem/progenitor cells, retroviral vectors containing the human erythropoietin receptor (hEpoR) gene were used to transduce the hEpoR gene into phenotypically sorted subsets of cells. CD34 , CD34++CD33-, and CD34++CD33+ populations of human cord blood, highly enriched for hematopoietic stem/progenitor cells, were sorted and plated as single cells per well in methylcellulose culture medium containing early acting growth factors in the presence or absence of Epo. The hEpoR gene was efficiently transduced into single high proliferative potential colony-forming cells (HPP-CFC) and multipotential (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]), erythroid (burst-forming unit-erythroid [BFU-E]), and granulocyte-macrophage (colony-forming unit-granulocyte-macrophage [CFU-GM]) progenitor cells. As expected in cultures grown in the absence of Epo, no BFU-E or CFU-GEMM colonies grew. In the presence of Epo, the hEpoR-gene transduced cells formed significantly more CFU-GEMM and BFU-E colonies than did the controls. A significant decrease in HPP-CFC colonies was also observed under these conditions. Little or no effect of hEpoR gene transduction was apparent in the numbers of CFU-GM colonies formed in the presence or absence of Epo. All of the above results were similar whether the cell populations assessed were CD34 or their CD33- or CD33+ subsets plated in the presence of growth factors at 200 cells/mL or after limiting dilution at 2 cells/well. These results suggest that the profile of detectable stem/progenitors can be altered by retrovirus-mediated expression of the hEpoR gene.

Antigens, CD↗
PubMed1996

The adhesion molecule E-cadherin and a surface antigen recognized by the antibody 9C4 are selectively expressed on erythroid cells of defined maturational stages.

The antigen expression of immature erythroid bone marrow cells was studied using two recently generated monoclonal antibodies (mAb), mAb 67A4 and 9C4, with specificities for the epithelial cell adhesion molecule E-cadherin (E-cad; mAb 67A4), and a novel 110 kDa differentiation antigen (mAb 9C4) with unknown molecular structure. Pappenheim staining of FACS-purified cells labeled with mAb 9C4 and anti-glycophorin A (GA) revealed that the majority of the 9C4+GA- and 9C4+GA+ cells consisted of erythroblasts. In contrast, the E-cad-positive population comprised normoblasts and erythroblasts. While the E-cad+GA- fraction contained mainly erythroblasts and basophilic normoblasts, the E-Cad+GA+ population was enriched in orthochromatic and polychromatophilic normoblasts. By colony assays of affinity column-purified cells it could be shown that erythroid colony forming units (CFU-E) were enriched and erythroid burst forming units (BFU-E) were depleted in the 9C4- and E-cad-positive fractions. Flow cytometric analysis of bone marrow cells double-labeled with mAb 67A4 and anti-CD71, anti-CD117, anti-CD34, or anti-GA revealed that about 90% of the E-cad-positive cells coexpressed CD71, about 70% were positive for CD117, about 50% for GA, and only about 5% coexpressed CD34. The expression pattern of 9C4 antigen was similar to that of E-Cad with the exception that only a minority of the 9C4-positive cells coexpressed GA. Lymphoid and myeloid markers were negative on both the E-Cad- and 9C4-positive populations. In these studies we describe the identification of a new mAb-defined antigen which is specifically expressed on erythroblasts and CFU-E(9C4) and demonstrate that E-Cad is not only expressed on epithelial cells but also on erythropoietic cells of defined maturational stages.

Antibodies, Monoclonal↗
PubMed1996

Phenotypic, molecular, and functional characterization of human peripheral blood CD34+/THY1+ cells.

A subset of mobilized CD34+ cells present in patient aphereses expresses Thy1 (CDw90). This population contains most long-term culture initiating cells, as assayed with a murine stromal cell line. It also contains a significant proportion of colony-forming unit granulocyte macrophage, but very few burst-forming unit erythroid. The limited differentiation towards the erythroid lineage is further confirmed by the absence of GATA-1 mRNA in the CD34+/Thy1+ subset, and by the low level of c-kit expression. The CD34+/Thy1+ subset appears phenotypically and functionally heterogeneous, a finding consistent with its high representation, compared to phenotypes such as CD34+/CD38-. Therefore, while at least some of CD34+/Thy1+ cells may be infectable by retroviral vectors, as shown by the presence of a transcript for the receptor for murine amphotropic retroviruses, the use of this selection strategy to specifically target human stem cells appears questionable.

Antigens, CD34↗
PubMed1996

Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2.

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.

Animals↗
PubMed1996

Expression of Fas/CD95 and Bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver.

The cell-surface expression and the functional status of the CD95/Fas antigen on primitive hematopoietic progenitors (PHPs) freshly isolated from human fetal liver (FL) were studied. PHPs were phenotypically defined as CD34++ CD38 -/+ cells. The most immature subfractions of PHPs, CD34++CD38- and CD34+2CD38+ FL cells, expressed CD95, whereas the more mature CD34++CD38++ and CD34+CD38++2 FL cells displayed low CD95 expression. Combinations of cytokines, such as kit ligand (KL) + interleukin-3 or KL + granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated the expression of CD95 on PHPs upon in vitro culture. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) further increased the CD95 expression induced by KL+GM-CSF. The hematopoietic potential of sorted CD34++lineage (lin)- CD95+ versus CD34++ lin-CD95-FL cells was compared by colony-forming unit-culture (CFU-C) assays performed in serum-deprived medium. Lin+ cells were composed of erythrocytes, monocytes, T cells, B cells, and natural killer cells. Our results indicated that both CD95- and CD95+ subsets contained pluripotent progenitors, generating myeloid and erythroid progenitors. The functional status of CD95 and the effects of TNF-alpha and IFN-gamma, cytokines known to induce CD95-mediated apoptosis, were analyzed by incubation of PHPs in the presence of anti-CD95 monoclonal antibodies (MoAbs). The effect of anti-CD95 MoAbs was measured by viable cell counting, flow cytometry, and CFU-C assays. A decrease of CFU-C numbers was observed in the presence of anti-CD95 MoAbs and TNF-alpha and/or IFN-gamma. However, whereas growth factor deprivation induced apoptosis of PHPs, cross-linking of CD95 did not lead to apoptosis of PHPs measured by flow cytometry and viable cell counting. The correlation of increased intracytoplasmic levels of bcl-2 with high levels of cell-surface CD34 and the presence of CD95 on fresh FL cells suggests that bcl-2 may be involved in protecting against CD95-mediated apoptosis of FL PHPs.

Antibodies, Monoclonal↗
PubMed1996

The effect of a hematopoietic-promoting factor (HPF) extracted from porcine kidney on the proliferation of human hematopoietic progenitor cells.

Hematopoietic-promoting factor (HPF), which was found in porcine kidney, has been demonstrated to act synergistically with colony-stimulating factor and erythropoietin on murine myeloid colony formation. We investigated the effect of HPF on the proliferation of human hematopoietic progenitor cells prepared from cord blood cells (CB) and peripheral blood cells (PB). HPF enhanced granulocyte colony-stimulating factor plus interleukin-3 and erythropoietin-induced colony formation, where the number of colonies were increased by 7.9-fold in CB and by 1.8-fold in PB, respectively. When we compared the effect of HPF with stem cell factor (SCF) on the colony formation derived from PB in serum-free cultures, HPF enhanced the number of erythroid burst-forming units (BFU-E) to the same extent as SCF. But the effect of HPF on promoting the growth of granulocyte-macrophage colony-forming units (CFU-GM) was less than SCF. When the enriched CD34+ cells from CB and PB were incubated in liquid culture with HPF and IL-3 for 7 days, CFU-GM was increased by 48-fold in CB, and by 25-fold in PB, respectively. The data demonstrate that HPF can potentiate expansion of hematopoietic stem cells to the same extent as SCF, and that the effects of HPF on hematopoitic stem cells differ from that of SCF.

Adult↗
PubMed1995

[The effect of STK-1 receptor (FLK2/FLT3) ligand on human erythropoiesis in vitro. Clinical implications].

The influence of a new discovered haematopoietic growth factor known as ligand of STK-1 receptor (FLK2/FLT3) on growth of human erytropoietic progenitors in vitro was evaluated. Studies were performed on bone marrow cells enriched in haematopoietic progenitors expressing CD 34 antigen in serum supplemented as in serum free medium. In conclusion STK-1 receptor ligand (STK-1L) does not influence the growth of human erythroid progenitors in vitro. Therefore STK-1L would not find practical application in future in vivo therapy as erythropoiesis stimulatory agent.

Cells, Cultured↗
PubMed1997

Thrombopoietin enhances proliferation and differentiation of murine yolk sac erythroid progenitors.

Thrombopoietin (TPO), the ligand for the receptor proto-oncogene c-Mpl, has been cloned and shown to be the critical regulator of proliferation and differentiation of megakaryocytic lineage. Initially, TPO was not considered to have the activity on hematopoietic lineages other than megakaryocytes. Recently, however, TPO was reported to enhance the in vitro erythroid colony formation from human bone marrow (BM) CD34+ progenitors or from mouse BM cells in combination with other cytokines. We examined the effects of TPO on the colony formation of hematopoietic progenitors in mouse yolk sac. TPO remarkably enhanced proliferation and differentiation of erythroid-lineage cells in the presence of erythropoietin (Epo). This effect was observed even in the absence of Epo. Compared with adult BM, yolk sac turned out to have relatively abundant erythroid and erythro-megakaryocytic progenitors, which responded to TPO and Epo stimulation. TPO similarly stimulated erythroid colony formation from in vitro differentiation-induced mouse embryonic stem (ES) cells whose hematopoietic differentiation status was similar to that of yolk sac. These findings help to understand the biology of hematopoietic progenitors of the early phase of hematopoiesis. Yolk sac cells or in vitro differentiation-induced ES cells would be good sources to analyze the TPO function on erythropoiesis.

Animals↗
PubMed1997

Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.

Several homeobox genes of the HOXA and HOXB clusters are expressed in primitive blood cells, suggesting a role for HOX genes in normal hematopoiesis. The HOXA9 gene is expressed in CD34+ marrow cells and in developing lymphocytes. We examined blood-forming organs of mice homozygous for an interrupted HOXA9 allele to determine if loss of HOX gene function is deleterious to hematopoiesis. HOXA9-/- mice have approximately 30% to 40% reductions in total leukocytes and lymphocytes (P < .001) and a blunted granulocytic response to granulocyte colony-stimulating factor (G-CSF). Homozygous mice have significantly smaller spleens and thymuses. Myeloid/erythroid and pre-B progenitors in the marrow are significantly reduced, but no significant decreases are noted in mixed colonies, day 12 colony-forming units-spleen (CFU-S), or long-term culture-initiating cells (LTC-IC), suggesting little or no perturbation in earlier progenitors. Heterozygous animals display no hematopoietic defects. The abnormalities in leukocyte production are transplantable, indicating that the defect resides in the hematopoietic cells. These studies demonstrate a physiologic role for a HOX gene in blood cell differentiation, with the greatest apparent influence of HOXA9 at the level of the committed progenitor.

Animals↗
PubMed1997

Mammalian homeobox B6 expression can be correlated with erythropoietin production sites and erythropoiesis during development, but not with hematopoietic or nonhematopoietic stem cell populations.

There has been increasing interest in the involvement of mammalian homeobox (HOX) genes in hematopoietic regulation. The HOX genes are clustered in 4 chromosomes in mice and humans. In general, 5' end HOX gene expression is predominant in hematopoietic stem cell populations, whereas 3' end HOX gene expression are primarily found in committed progenitor cells. Furthermore, HOX genes of the A cluster are generally found in myelomonocytic cells, B cluster genes in erythropoietic cells, and C cluster genes in lymphoid cells. The results presented here concentrate on a single gene, namely HOX B6. Preliminary observations using whole mount in situ hybridization showed that both HOX B6 and erythropoietin (EPO) gene expression occurred in exactly the same areas of the 8.5-day mouse embryo. As a consequence, we studied the expression of HOX B6 and EPO gene expression from 6.5 to 19.5 days of gestation, in the neonate, and in the adult. It was found that the sequential transfer of erythropoiesis in different organs during development was followed by a similar transfer of HOX B6 and EPO gene expression. Between days 16.5 and 17.5, both HOX B6 and EPO gene expression decrease in the fetal liver, even though hepatic erythropoiesis continues to decline and is transferred to the fetal spleen. Precisely at this time point, HOX B6 and EPO gene expression are transferred to both the fetal spleen and fetal kidney. However, surprisingly, expression of both genes increases again in the fetal liver just before birth. HOX B6 is expressed in cells from in vitro erythropoietic colonies (colony-forming unit-erythroid and burst-forming unit-erythroid) and TER-119+ erythroid cells but not in hematopoietic or nonhematopoietic stem cell populations. When the latter two populations are allowed to differentiate into erythropoietic cells, HOX B6 and erythroid-relevant markers are expressed. The results indicate that HOX B6 is intimately involved in the regulation of the erythropoietic system and could be a marker for this lineage.

Animals↗