Targeting erythroblast-specific apoptosis in experimental anemia
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Erythrocyte production is regulated by balancing precursor cell apoptosis and survival signaling. Previously, we found that BH3-only proapoptotic factor, Nix, opposed erythroblast-survival signaling by erythropoietin-induced Bcl-xl during normal erythrocyte formation. Since erythropoietin treatment of human anemia has limitations, we explored the therapeutic potential of abrogating Nix-mediated erythroblast apoptosis to enhance erythrocyte production. Nix gene ablation blunted the phenylhydrazine-induced fall in blood count, enhanced hematocrit recovery, and reduced erythroblast apoptosis, despite lower endogenous erythropoietin levels. Similar to erythropoietin, Nix ablation increased early splenic erythroblasts and circulating reticulocytes, while maintaining a pool of mature erythroblasts as erythropoietic reserve. Erythrocytes in Nix-deficient mice showed morphological abnormalities, suggesting that apoptosis during erythropoiesis not only controls red blood cell number, but also serves a “triage” function, preferentially eliminating abnormal erythrocytes. These results support the concept of targeting erythroblast apoptosis to maximize erythrocyte production in acute anemia, which may be of value in erythropoietin resistance.
KeywordsApoptosis Anemia Erythropoiesis Erythropoietin
Supported by NHLBI HL59888, HL77101 (to G.W.D.), the American Heart Association (Scientist Development Grant to A.D.), and the U.S. Department of Veterans Affairs. The authors declare no competing financial interests. Author contributions: A.D. designed and performed research, analyzed data and wrote paper, A.G.K. performed research and analyzed data, D.C. performed research and analyzed data, H.G. performed research and analyzed data, T.A.K. performed research and analyzed data; and G.W.D. designed and performed research, analyzed data and wrote paper.
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