Accessory Cells In Normal and Stress Erythopoiesis

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DESCRIPTION (provided by applicant): Erythropoiesis is ineffective in myelodysplasia (MDS) and the anemia of chronic inflammation (ACI) because erythroid progenitor cells are normal in number, but they do not mature appropriately. In hematopoietic organs, erythroid progenitor cells adhere to a central macrophage forming erythroblastic islands. Interactions between the erythroid progenitor cells and central macrophage are necessary for maturation of both the erythroblasts and the nascent reticulocytes formed by erythroblast enucleation. Inflammatory cytokines are implicated in the pathophysiology of MDS and ACI. I hypothesize that direct interactions between erythroid progenitor cells and macrophages are necessary for erythroid cell maturation and that specific inflammatory cytokines disrupt these interactions, leading to ineffective erythropoiesis. I also hypothesize that after reticulocytes enter the circulation, further interactions between reticulocytes and splenic macrophages, stroma, or vascular endothelium are necessary for complete maturation of the reticulocytes into erythrocytes. In anemias due to hemolysis and blood loss, erythropoietic stress causes premature entry of reticulocytes into the circulation and may lead to pathologic erythrocyte development due to altered erythroid cell-macrophage interactions. The proposed research will use an in vitro system of murine proerythroblast differentiation to evaluate the effects of co-culture with bone marrow or splenic macrophages on erythroblast proliferation, apoptosis, expression of cell surface molecules, and reticulocyte formation. Reticulocytes derived in vitro from erythroblasts in this system as well as circulating stress reticulocytes from phlebotomized, anemic mice will be co-cultured with splenic macrophages, a splenic stromal cell line, or an endothelial cell line to evaluate the reticulocytes for formation of biconcave erythrocytes and expression of cell surface molecules. Inflammatory cytokines will be added to co-cultures to measure inhibitory effects on erythroblast and reticulocyte maturation. ln vivo maturation of circulating stress reticulocytes will be compared in splenectomized and sham-operated mice. The proposed research will enhance our understanding of and provide potential treatment approaches for the ineffective erythropoiesis of MDS and ACI. Similarly, this research will help in understanding and treating the impaired interactions between circulating reticulocytes and accessory cells in hemolytic or blood loss anemias.