? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK077056-01
Application #
7190367
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$125,091
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Rhodes, Melissa M; Koury, Stephen T; Kopsombut, Prapaporn et al. (2016) Stress reticulocytes lose transferrin receptors by an extrinsic process involving spleen and macrophages. Am J Hematol 91:875-82
Rhodes, Melissa M; Kopsombut, Prapaporn; Bondurant, Maurice C et al. (2008) Adherence to macrophages in erythroblastic islands enhances erythroblast proliferation and increases erythrocyte production by a different mechanism than erythropoietin. Blood 111:1700-8