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PubMed1990

Platelet factor 4 inhibits human megakaryocytopoiesis in vitro.

Platelet factor 4 (PF4) is a multifunctional protein specific to platelets, synthesized in megakaryocytes and stored in alpha granules. This report of our work shows that PF4 potently inhibits human megakaryocyte colony formation in vitro. Colony formation by megakaryocyte progenitor cells from normal bone marrows was studied using the plasma clot culture system and indirect immunoperoxidase staining. Nonadherent mononuclear cells were co-cultured with various concentrations (0 to 20 micrograms/mL) of highly purified human PF4. Statistically significant inhibition of three classes of megakaryocyte progenitor cells, the mixed colony forming unit-megakaryocytes (mCFU-MK), the burst forming unit-megakaryocytes (BFU-MK), and the colony forming unit-megakaryocytes (CFU-MK), was seen at a PF4 concentration of 2.5 micrograms/mL or greater. PF4 had no effect on erythroid (BFU-E) and granulocyte/macrophage (CFU-GM) colony formation except at high concentration (5 micrograms/mL for BFU-E and 10 micrograms/mL for CFU-GM). When a concentration of 5 micrograms/mL PF4 was added at various time points during marrow culture, a reduction of megakaryocyte colony formation also occurred. In the presence of PF4 2.5 micrograms or 5 micrograms/mL, the percentage of mature type of colonies was found to be decreased compared with cultures with no added PF4. These data demonstrate that PF4 inhibits both proliferation and maturation of megakaryocyte progenitor cells in vitro and suggest that PF4 may play a role in autoregulating human megakaryocytopoiesis.

Bone Marrow↗
PubMed1990

Accelerated postirradiation recovery of hematopoietic marrow following priming with low doses of vincristine.

The present investigation is a continuation of efforts to characterize the radioprotective potential of priming with vincristine (VcR). In this study, the postirradiation recovery kinetics of the marrow's hematopoietic stem cell, progenitor cell, and stromal cell compartments were monitored following exposure to a range of sublethal radiation doses to determine (a) the optimal VcR/radiation intertreatment interval for achieving maximal hematopoietic protection, (b) whether this optimal interval is influenced by the dose of radiation administered, and (c) whether the radioprotection observed involves the hematopoietic stroma. The results demonstrate that the degree of radioprotection observed was significantly influenced by the scheduling of the VcR priming dose with respect to the radiation exposure. An intertreatment interval of 24 h provided maximal radioprotective benefit irrespective of the radiation dose administered. Additionally, the radioprotection following VcR priming appeared to be more the result of an accelerated recovery in the hematopoietic stem cell and progenitor cell compartments than a change in their intrinsic radiosensitivity. The data also suggest that this accelerated recovery was not a consequence of greater radioprotection of marrow stroma. Finally, the radioprotection observed following VcR priming did not appear to involve a selective lineage response by either the erythroid or the granulomonocytic progenitor compartments.

Animals↗
PubMed1990

[Erythroid colonies derived from BFU-E from the bone marrow in a patient with type I congenital dyserythropoietic anemia].

The findings of in vitro culture of bone-marrow BFU-E from a patient with type I dyserythropoietic anaemia are reported, scarce data being seemingly available in the literature. The number of BFU-E in the culture was increased four-fold with respect to the normal values. The morphologic study of the colonies showed in all cases varying number of erythroblasts with internuclear bridges (5-20%). Upon ultrastructural examination of the colonies, a great number of erythroblasts exhibited morphologic alterations, spongy chromatin and internuclear bridges being commonest. These findings suggest that an alteration of the progenitor erythroid cells exists in type I dyserythropoietic anaemia, whereas the morphological defects appreciated show great variation in the progeny of each BFU-E.

Adult↗
PubMed1989

[Study on the uremic protein binding inhibitors as uremic toxin: toxic effect on erythroid colony formation, lymphocyte blast formation and renal function].

Certain uremic metabolites are recognized to have high affinity to serum protein and some of them have been identified as hippuric acid (HA), quinolinic acid (QA) and indoxyl sulfate (IS). Cell toxicity and effect on renal function of these substances were examined by means of erythroid colony formation, lymphocyte blast formation and isolated perfused rat kidney. These substances inhibited the binding of diphenylhydantoin to albumin, depending on the concentration of the substances. At the same concentration of 10 mg/dl, IS was most potent and QA was the second. QA and IS suppressed the erythroid colony formation, depending on the concentration of QA and IS. On the other hand, HA had no suppressive effect even at the higher concentration. The suppressive effect of QA and IS were attenuated by increasing erythropoietin concentration. QA and IS had strong suppressive effect of lymphocyte blast formation and interleukin 2 production at the concentration of uremic serum. However, they did not suppress the increase of intracellular calcium concentration of lymphocytes after stimulation by mitogen. This might indicate the possibility that these substances act not only on cell surface but on intracellular protein. HA and IS inhibited para-aminohippurate secretion and QA suppressed tubular reabsorption of sodium in isolated perfused rat kidney. These results show that the uremic protein binding inhibitors may influence renal regulation of fluid and electrolyte homeostasis. It is concluded that some of the protein binding inhibitors have toxic effects on cell function of various tissues and play a role in pathophysiology of uremia.

Animals↗
PubMedDate not supplied

Direct effects of IL-4 on the in vitro differentiation and proliferation of hematopoietic progenitor cells.

The purpose of this study was to analyze the effects of recombinant human interleukin 4 (IL-4) on the differentiation and proliferation in vitro of human granulocyte/macrophage (GM) and erythroid progenitors. IL-4 was added to either fetal bovine serum (FBS)-supplemented or to FBS-deprived cultures of unfractionated human marrow cells or marrow cells depleted of adherent and/or T cells. Paradoxical effects similar to those reported in the murine system were detected in these experiments. In FBS-supplemented cultures, IL-4, which had no effect on the growth or erythroid bursts (from burst-forming cells; BFU-E) detected in the presence of Epo alone, decreased by 46% the number of erythroid bursts detected in the presence of Epo and phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). In contrast, in FBS-deprived cultures, IL-4 increased by 30-700% the number of erythroid bursts in cultures containing Epo alone or containing Epo, IL-3, and GM-CSF. The stimulatory effect of IL-4 on erythroid burst growth under FBS-deprived conditions was particularly evident when adherent cells were removed. Under the conditions investigated, IL-4 had little effect on the growth of GM colonies. In FBS-deprived suspension cultures of nonadherent, T-cell-depleted marrow cells, IL-4 maintained both the number of BFU-E and CFU-GM for at least 8 days. In these cultures, IL-4 antagonized the capacity of IL-3 to increase the number of BFU-E but IL-4 and IL-3 acted together to maintain the number of CFU-GM. To determine if IL-4 acted directly or indirectly, its effects on the growth of factor-dependent subclones of the murine progenitor cell line 32D were analyzed. Three subclones were studied: the original IL-3-dependent clone 32D cl.3, the Epo-dependent erythroid clone 32D Epo-1, and the G-CSF-dependent myeloid clone 32D G-1. IL-4 alone failed to induce colony growth from these cell lines. However, IL-4 inhibited by 25% the number of colonies formed by 32D cl.3 in the presence of IL-3 while increasing by 25% and 25-50% the number of colonies formed by 32D Epo-1 and 32D G-1 in the presence of Epo or G-CSF, respectively. These results indicate that human IL-4, as its murine counterpart, is a multilineage growth factor with paradoxical effects which are mediated by the direct action of IL-4 on progenitor cells.

Cell Differentiation↗
PubMed1989

Morphology of interactions of the haematopoietic microenvironment with the haematopoietic cells in erythroid spleen colonies.

The morphology of the interactions of the cells of the haematopoietic microenvironment with haematopoietic cells was studied in exogenous erythroid spleen colonies formed in mice, on the fifth and eighth day after their irradiation with a lethal dose of gamma rays and bone marrow transplantation. The characteristic type of stromal cell interacting with less mature cells of the erythroid series was a dark, branching reticular cell. The typical structural interaction of the reticular cells with erythroblasts was the formation of very long, fine cytoplasmic processes by the reticular cells. The processes were in close contact with the erythroblasts and formed a three-dimensional network stretching long distances from the nucleus of the reticular cells. Other cells of the haematopoietic microenvironment, in contact chiefly with poly- and ortochromic erythroblasts, were macrophages and the two together formed typical erythroblastic islands. In places, the macrophages and erythroblasts formed close, firm contacts by means of their cytoplasmic membranes. These morphological observations support the conception that close functional cooperation exists between the cells of the haematopoietic microenvironment and the haematopoietic cells in differentiation and proliferation processes in the haematopoietic tissue of spleen colonies.

Animals↗
PubMed1989

c-myc and c-myb oncoproteins during induced maturation of myeloid and erythroid human leukemic cell lines.

c-myc and c-myb mRNAs have been found to be tightly regulated during hemopoietic differentiation. We have studied nuclear c-myc and c-myb oncoproteins through the cell cycle, during macrophage, granulocyte, erythroid, and megakaryocytic differentiation of KG1, HL60, and HEL cells. p62c-myc and p75c-myb content of propidium iodide-stained nuclei was quantitated by flow cytometry using fluoresceinated antibodies CT14-G4 and MB4.3, respectively. In uninduced cells p62c-myc content is highest in HL60, followed by HEL, then KG1, while p75c-myb is highest in HEL, followed by HL60 and KG1. All lines showed a less than 2-fold increment in both oncoproteins over the cell cycle. Macrophage induction of KG1 and HL60 resulted in early increase in both oncoproteins, followed by a decline to less than starting values by 48 h, concurrent with a reduction of S phase cells and the appearance of adherent alpha-naphthyl acetate esterase-positive cells. p62c-myc changes were more pronounced in HL60 and p75c-myb changes in KG1. Different patterns of oncoprotein expression were found when different inducing agents were used for granulocyte differentiation of HL60. Under all conditions, however, both oncoproteins declined to basal levels before granulocyte maturity. Hemin-induced erythroid differentiation of HEL to hemoglobin-containing cells resulted in biphasic p62c-myc and p75c-myb kinetics. In contrast, dimethyl sulfoxide-induced megakaryocytic differentiation of HEL was accompanied by an early and steady decline in both oncoproteins. Despite considerable reduction in oncoprotein levels, HEL cells were still actively cycling at 120 h. It appears that c-myc and c-myb proteins decline with differentiation, well before proliferation ceases in some lineages. The kinetics of the decline differ between the two oncogenes and vary with the lineage induced and the nature of the inducing agent used. The cell cycle distribution of the oncoproteins does not change during maturation. These data suggest disparate roles for c-myc versus c-myb during hemopoietic differentiation and the existence of multiple signal transduction pathways for down-regulation of these genes.

Antibodies, Monoclonal↗
PubMed1989

Spleen stromal cell lines selectively support erythroid colony formation.

Mouse stromal cell lines (MSS lines) have been established from the spleens of newborn mice in culture at a low serum concentration. These MSS lines support the proliferation and differentiation of the erythroid progenitor cells from mouse fetal livers and bone marrow in a semisolid medium in the presence of erythropoietin. Larger colonies of over 1,000 benzidine-positive erythroid cells were developed from the fetal liver cells on the MSS cell layers after 6 days of incubation. These layers also support the maturation of the erythroid cells since the enucleation process of the latter was observed in large erythroid colonies. Metabolically active MSS cells are apparently required to support the proliferation and differentiation of the erythroid progenitor cells, because neither the MSS cells inactivated with fixation nor the conditioned media of MSS cells promoted the erythroid colony formation. These studies demonstrate that MSS lines specifically support the proliferation and differentiation of the erythroid progenitor cells in vitro and that stroma cells may have a critical function in blood formation in the mouse spleen.

Animals↗
PubMed1994

Selection and characterization of early hematopoietic progenitors using an anti-CD71/S06 immunotoxin.

Most recently reported methods to select early hematopoietic cells basically rely on the depletion of committed progenitors. This task is generally accomplished by laborious procedures, which are sometimes difficult to reproduce. To simplify the selection method, we took advantage of the expression of the transferrin receptor (CD71) by proliferating committed progenitors and the lack of CD71 on noncycling immature progenitors. A monoclonal antibody (MAB) reactive with CD71 has been conjugated to the Saponaria officinalis seed ribosome-inactivating protein (SO6). The immunotoxin (IT) complex was used at increasing concentrations on normal non-phagocytizing bone marrow cells. A complete and reproducible killing effect on myeloid (colony-forming unit-granulocyte/macrophage [CFU-GM]) and erythroid (burst-forming unit-erythroid [BFU-E]) progenitors was observed for IT concentrations of 1 x 10(-7) M. Unconjugated SO6 or anti-CD71 MAB had no effect on cell growth and viability. IT-resistant cells were able to generate CFU-GM after 7, 14, and 21 days of suspension culture in the presence of 5637 CM. Maximal CFU-GM values were obtained at day 21 and nearly approached the pretreatment values (mean 2587 vs. 3877 CFU-GM/mL). Growth factor enhancement of CFU-GM yield was obtained only by stem cell factor (SCF) at day 7; SCF, as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), had an enhancing effect at days 14 and 21. IT toxicity on highly immature progenitors was ruled out by evaluating the growth of long-term culture-initiating cells (LTC-IC) from IT-treated cultures. LTC-IC frequency was found to be 1 out of 1506 seeded cells, which is within the range of normal untreated BM cells. In conclusion, anti-CD71 IT allows a simple and complete depletion of committed progenitors while sparing immature hematopoietic cells. The high CD71 expression by leukemic cells makes the procedure potentially suitable for in vitro purging.

Antibodies, Monoclonal↗
PubMed1994

Sl/Sld hematopoietic progenitors are deficient in situ.

The hematopoietic microenvironment in Steel mutant mice does not support erythropoiesis, megakaryocytopoiesis, or mast cell generation. The question of whether Steel hematopoietic progenitors are present in normal numbers has never been convincingly addressed. In this report, Sl/Sld marrow cells were assessed for long-term competitive repopulation ability in vivo and for short-term growth in vitro. In vivo repopulation assays indicate that the Sl/Sld progenitors are at a distinct disadvantage when they compete against congenic genetically marked +/+ cells in a +/+ host. On the other hand, the Steel erythroid colony-forming cells (CFU-E) respond normally to erythropoietin (Epo) in vitro and are present at normal frequency. Because the Steel marrow is less cellular than normal marrow, the absolute number of CFU-E is decreased. Results suggest that the absence of membrane-bound Steel factor in the mutant donor has a direct effect on Steel hematopoietic progenitors, which is not alleviated during growth for over 6 months in a normal microenvironment. The anomaly does not seem to directly affect the frequency of more mature adult erythroid progenitors.

Animals↗
PubMed1994

Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells.

Umbilical cord blood (CB) has been identified as a potential source of hematopoietic stem cells suitable for clinical transplantation. We used long-term cord blood cultures (LTCBC) to evaluate the hematopoietic potential of populations of umbilical CB cells phenotypically defined and isolated by flow cytometry. LTCBC initiated with CD34+HLA-DR+ and CD34+HLA-DR- CB cells were examined over a period of 8 weeks for the production of assayable burst-forming units-erythroid (BFU-E), colony-forming units-granulocyte/macrophage (CFU-GM), and colony-forming units-mixed (CFU-GEMM) in response to repeated additions of stem cell factor (SCF), interleukin-3 (IL-3), IL-6, and either erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The LTCBC-initiating cell (LTCBC-IC) appeared to be present among CD34+HLA-DR+ cells, in contrast to our previous findings in adult bone marrow (BM), where the long-term culture initiating cells were shown to be CD34+HLA-DR-. In addition, production of BFU-E, CFU-GM, and CFU-GEMM in CB CD34+HLA-DR+ cells displaying low uptake of the supravital dye rhodamine 123 (Rh123) exceeded those detected in the fraction of cells with high uptake of Rh123. Furthermore, on day 21 of LTCBC, the production of the high proliferative potential colony-forming units (HPP-CFC) by CB CD34+HLA-DR+Rh123dull cells was five-fold greater than that detected in cultures initiated with their Rh123bright counterparts. Collectively, these data show that, contrary to what has been documented in adult human BM, LTCBC-IC and presumably CB cells capable of in vivo engraftment reside in the CD34+HLA-DR+Rh123dull fraction of CB. Although the functional significance of these differences between the in vitro behavior of phenotypically defined populations of CB and BM remains to be determined, these findings constitute an objective parameter with which the suitability of CB for clinical transplantation may be assessed.

Antigens, CD↗
PubMed1993

Different responses of human marrow and circulating erythroid progenitors to stem cell factor, interleukin-3 and granulocyte/macrophage colony-stimulating factor.

The effects of recombinant human stem cell factor (SCF/c-kit ligand), interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) on erythroid colony formation by non-phagocytic mononuclear cells (MNC) and CD34+ cells derived from normal human bone marrow (BM), peripheral blood (PB) and umbilical cord blood (CB) were studied using a methylcellulose culture containing recombinant human erythropoietin (Epo). BM-MNC generated the largest number of total erythroid colonies consisting of erythroid bursts and erythroid mixed colonies (E-Mix) in the presence of SCF, whereas PB-MNC produced the largest number with IL-3. No additive effect between SCF and IL-3 was observed in the erythroid colony formation by BM- or PB-MNC. These observations were reproducible in cultures with several independent samples and purified CD34+ cells, suggesting that in normal human adults the erythroid progenitors supported by SCF alone mainly reside in the BM but those supported by IL-3 alone are mainly circulating. IL-3 was the most potent promoter of the total erythroid colony formation by CB-MNC, but it had no cooperation with SCF. In contrast, SCF supported large numbers of E-Mix and showed significant cooperative activity with IL-3 in E-Mix formation. These findings were also confirmed using independent specimens and CD34+ cells. Outstanding E-Mix formation by the CB cells indicated that newborn infants contain significantly more immature circulating erythroid progenitors than adults. These observations will stimulate interest in the role of the c-kit-SCF system as an adhesion molecule in the ontogenetic development of hemopoiesis.

Adult↗
PubMed1994

Mast cell growth factor modulates CD36 antigen expression on erythroid progenitors from human bone marrow and peripheral blood associated with ongoing differentiation.

To study the differentiation process of erythroid progenitors from normal human bone marrow and peripheral blood, CD34/CD36 sorted cells were cultured in the presence of Erythropoietin (Epo) and Epo plus mast cell growth factor (MGF). The CD34+/CD36- cell fraction from bone marrow supported 74 +/- 33 erythroid burst forming units (BFU-E)/10(4) cells (mean +/- SD, n = 4) in the presence of Epo, which increased 2.1-fold by coculturing with MGF. However, erythroid colony-forming units (CFU-E) were not cultured from the CD34+/CD36- cell fraction. In contrast, the CD34-/CD36+ cell fraction supported CFU-Es in the presence of Epo (152 +/- 115/10(5)) or Epo plus MGF (180 +/- 112/10(5)), whereas BFU-Es were hardly noticed. However, the transition of the BFu-E to CFU-E was observed by incubating CD34+/CD36- cells (10(4)/100 microL) in suspension with Epo plus MGF for 7 days followed by Epo in the colony assay. This was reflected by the appearance of CD34-/CD36+/Glycophorin A+/CD14- cells. In addition high numbers of CFU-Es (1,000 +/- 150, n = 4) were cultured from this cell fraction. In contrast to bone marrow erythroid progenitors, no peripheral blood CFU-Es were cultured from either the CD36+ or CD36- fraction, whereas BFU-Es were predominantly present in the CD36+ fraction. However, the CD34+ progenitor cell from peripheral blood did have intrinsic capacity to differentiate to CFU-Es because CD34+/CD36- cells incubated with Epo plus MGF for 7 days and followed by Epo in the colony assay, supported high numbers of CFU-Es (1,200 +/- 400, n = 3). To study whether additional growth factors have similar effects on erythroid progenitors, experiments were performed with interleukin 1 (IL-1), IL-3, and IL-6. IL-1 and IL-6 did not modulate the Epo supported proliferation and differentiation. In contrast, IL-3 in the presence of Epo did support CFU-Es, from CD34+/CD36- cells after 7 days in suspension culture. However, flow cytometry analysis showed that Epo plus IL-3 not only supported CD34-/CD36+/Glycophorin A+ cells but also CD36+/CD14+ cells, indicating the differentiation along different cell lineages. In summary, the data show a phenotypic distinction between bone marrow and peripheral blood erythroid progenitors with regard to CD36 expression. In addition, the results suggest that Epo plus MGF or IL-3 and preincubation in suspension culture are prerequisites for the transition of the BFU-E to the CFU-E.

Antigens, CD↗
PubMed1994

Evidence for nonclonal hematopoietic progenitor cell populations in bone marrow of patients with myelodysplastic syndromes.

Clonality of marrow hematopoietic progenitor cells in myelodysplastic syndromes (MDS) was analyzed by X-chromosome inactivation pattern using polymerase chain reaction (PCR). Five female patients were included in this study; two with refractory anemia (RA) and three with RA with excess blasts (RAEB). They were heterozygous for BstXI restriction fragment length polymorphisms (RFLP) of the X-chromosome-linked phosphoglycerate kinase (PGK) gene. In each patient, erythroid and nonerythroid colonies, grown in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), exhibited no remarkable difference in clonal constitution. Two patients showed only one methylation pattern, suggesting the monoclonal origin of hematopoietic progenitor cells. Colonies of two other patients exhibited predominant and minor methylation patterns in PGK gene, indicating that nonclonal progenitor cells remain a minor population. The bone marrow of one patient appeared to contain a greater proportion of nonclonal progenitors. Stem cell factor (SCF), a potent colony-stimulating factor, enhanced both erythroid and nonerythroid colony formation. However, it did not notably alter the clonal constitutions. We conclude that nonclonal hematopoietic progenitor cells can persist in a substantial number of MDS patients.

Aged↗
PubMed1994

Adhesion of committed human hematopoietic progenitors to synthetic peptides from the C-terminal heparin-binding domain of fibronectin: cooperation between the integrin alpha 4 beta 1 and the CD44 adhesion receptor.

Close interaction of human hematopoietic progenitors with the bone marrow microenvironment is important for the ordered progression of human hematopoiesis. Progenitor cell adhesion to stroma has a complex molecular basis, involving various cell-extracellular matrix and cell-cell interactions. We have previously shown that adhesion of colony-forming cells (CFC) to fibronectin, present in stromal extracellular matrix, involves multiple sites, including two heparin-binding synthetic peptides (FN-C/H I and FN-C/H II) and the alpha 4 beta 1 integrin-binding peptide CS1. These synthetic peptides are located in close proximity in the type III repeat 14 and the immediately adjacent type IIIcs region of fibronectin. In the current study, we evaluate receptors expressed by CFC responsible for their adhesion to fibronectin. We show that the alpha 4 beta 1 integrin mediates adhesion to CFC to the peptides FN-C/H I and CS1. Adhesion of CFC to fibronectin is also mediated by proteoglycans, because removal of cell surface chondroitin-sulfate proteoglycans resulted in decreased adhesion of CFC to FN-C/ I and FN-C/H II. The core protein of this proteoglycan was identified by immunoprecipitation as a 90-kD member of the CD44 group of adhesion molecules. Interestingly, although the proteoglycan core protein failed to adhere to FN-C/H II affinity columns, anti-CD44 monoclonal antibodies blocked CFC adhesion to FN-C/H II, indicating that these monoclonal antibodies may interfere with core protein-mediated intracellular signalling. Finally, we show that CD44 and alpha 4 beta 1 may cooperate in establishing progenitor adhesion, because anti-CD44 antibodies potentiated the adhesion-inhibitory effects of suboptimal concentrations of anti-alpha 4 or anti-beta 1 monoclonal antibodies. These results provide a working model for progenitor cell recognition of fibronectin (and possibly the marrow micro-environment) in which the coordinated action of integrins and cell surface proteoglycans is necessary for cell adhesion. This model can now be used to study the complex relationship between progenitor cell adhesion and the regulation of their proliferation and differentiation.

Amino Acid Sequence↗
PubMed1995

Proliferation and differentiation of myelodysplastic CD34+ cells: phenotypic subpopulations of marrow CD34+ cells.

In a search for a mechanism to explain the impaired growth of progenitor cells in patients with myelodysplastic syndromes (MDS), marrow CD34+ cells were purified up to 94.9% +/- 4.2% for normal individuals and 88.1% +/- 17.6% for MDS patients, using monoclonal antibodies and immunomagnetic microspheres (MDS CD34+ cells). Phenotypic subpopulations of these CD34+ cells were analyzed for CD38, HLA-DR, CD33, CD13, CD14, CD41 and CD3 plus CD19, in association with proliferative and differentiative capacities. The 15 studies performed included 12 MDS patients. Coexpression rate of CD13 significantly increased in the MDS CD34+ cell population with a value of 91.4% +/- 11.6% and ranging from 60.3% to 100%, and exceeded 99% in four studies, whereas that of normal CD34+ cells was 49.9% +/- 15.8%, ranging from 28.2% to 70.1% (P < .001). Coexpression rate of CD38, HLA-DR, CD33, CD14, and CD3 plus CD19 in MDS CD34+ cells did not significantly differ from that of normal CD34+ cells. The total number of colonies and clusters grown from 100 normal marrow CD34+ cells was 40.4 +/- 8.6, the range being from 27.2 to 50.3; this varied in MDS marrow CD34+ cells with a value of 34.0 +/- 28.7, the range being 0 to 95.9. The lineage of colonies and clusters promoted by MDS marrow CD34+ cells was predominantly committed to nonerythroid with impaired differentiation in 13 of 15 studies (87%). CD13 is first expressed during hematopoiesis by colony-forming unit granulocyte-macrophage and is absent in erythroid progenitors. Therefore, this study provides direct evidence for the lineage commitment of MDS CD34+ cells to nonerythroid with impaired differentiation and explains the mechanism of nil or low colony expression of MDS progenitor cells to erythroid lineage.

Aged↗
PubMed1995

Effects of rhIL-1 alpha, rhIL-1 beta, and rhIL-1 receptor antagonist on erythroid progenitors (CFU-E and BFU-E) in human bone marrow.

Interleukin-1 (IL-1) is known to promote the production of colony-stimulating factor (CSF) and to possess the ability to protect the bone marrow suppression in granulocyte-macrophage (GM) series associated with radiotherapy or chemotherapy. There are conflicting reports concerning the action of IL-1 on erythroid progenitors, however, and no consensus has been established. In the present study, the influences of recombinant human IL-1 alpha (rhIL-1 alpha), rhIL-1 beta, and rhIL-1 receptor antagonist (rhIL-1ra) on erythroid progenitors (colony-forming units-erythroid, CFU-E; and burst-forming units-erythroid, BFU-E) in human bone marrow were studied. rhIL-1 alpha and rhIL-1 beta (1-1000 pg/mL) enhanced the CFU-E and BFU-E growth in human nonadherent (NA) bone marrow cells. rhIL-1 alpha and rhIL-1 beta also stimulated the formation of CFU-E and BFU-E in the NA and T cell-depleted bone marrow fraction. Moreover, rhIL-1 alpha and rhIL-1 beta enhanced the CFU-E and BFU-E in the CD34+ bone marrow cell fraction. These data and the results of limiting dilution analysis indicate that the stimulatory effect of IL-1 may consist of direct actions on erythroid progenitors. The enhancing effect of rhIL-1 alpha and rhIL-1 beta on erythroid progenitors was inhibited by rhIL-1ra. These data suggest that the stimulatory effect of IL-1 on CFU-E and BFU-E is mediated via the IL-1 receptor.

Antigens, CD↗