Erythroblasts adhere to central macrophages forming erythroblastic islands in hematopoietic tissues, but the function of these islands is not understood. Murine erythroblastic islands were reconstituted in vitro with macrophages and developmentally synchronous proerythroblasts. Erythroblasts cocultured with macrophages proliferated 3-fold greater than erythroblasts cultured alone. Direct contact with the macrophages was necessary for this enhanced erythroblast proliferation, which resulted from decreased transit time in the G 0 /G 1 phase of cell cycle. Increased erythroblast proliferation in erythroblastic islands occurred over a wide range of erythropoietin concentrations and was the result of a mechanism different from the antiapoptotic effect of erythropoietin. Erythroblasts adherent to macrophages had slightly delayed enucleation, but otherwise differentiation was similar to erythroblasts cultured alone or those that became nonadherent in cocultures. These results suggest a mechanism for the development of anemias associated with abnormal macrophage function and for reduced responsiveness of those anemias to erythropoietin therapy.
IntroductionIn hematopoietic tissues, the hematopoietic progenitor and precursor cells are in close contact with various nonhematopoietic stromal cells. Potential roles of these interactions include modulation of hematopoietic cell survival, proliferation, and differentiation. During late stages of erythropoiesis, the hematopoieticstromal cell interaction has been identified in a specific structure termed the erythroblastic island, which is composed of erythroid progenitor and precursor cells surrounding a single macrophage. 1 Erythroblastic islands are increased in patients with hemolytic anemias and decreased in hypertransfused animals. 2 Bessis et al 3 proposed that an erythroblastic island forms when a single macrophage and colony forming unit-erythroid (CFU-E) associate and the CFU-E undergoes 4 to 5 divisions, producing 16 or 32 erythroblasts bound to each macrophage. Hematopoietic cells proliferated more in clusters with macrophages than when they were dissociated from stromal macrophages and cultured alone. 4 A specific proliferative effect of macrophages on erythroid cells was not demonstrated because these clusters of hematopoietic cells contained other cell types in addition to erythroid cells. Using human blood-derived macrophages and erythroid cells to reconstitute erythroblastic islands, Hanspal and Hanspal 5 demonstrated increased accumulation of cultured erythroid cells that had direct contact with macrophages, but it was not determined whether this increase was the result of decreased apoptosis, increased proliferation, or both.Erythropoietin (EPO) is the hormone that permits survival of erythroid progenitors from CFU-E through early proerythroblast stages of differentiation by preventing their apoptosis. 6 EPO is produced by the kidneys in response to hypoxia, and the circulating EPO concentration is the main regulator of erythroid progenitor numbers. How this ...
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