Role of Gas6 in erythropoiesis and anemia in mice
Anne Angelillo-Scherrer, … , Edward M. Conway, Peter Carmeliet
Anne Angelillo-Scherrer, … , Edward M. Conway, Peter Carmeliet
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):583-596. https://doi.org/10.1172/JCI30375.
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Research Article Hematology

Role of Gas6 in erythropoiesis and anemia in mice

Abstract

Many patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest–specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.

Authors

Anne Angelillo-Scherrer, Laurent Burnier, Diether Lambrechts, Richard J. Fish, Marc Tjwa, Stéphane Plaisance, Rocco Sugamele, Maria DeMol, Eduardo Martinez-Soria, Patrick H. Maxwell, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Marc Chanson, Désiré Collen, Shozo Izui, Marc Schapira, Edward M. Conway, Peter Carmeliet

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Figure 7

Gas6 is required for adhesion of erythroblasts.

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Gas6 is required for adhesion of erythroblasts. (A) Adherence of WT vers...
(A) Adherence of WT versus Gas6–/– erythroblasts to fibronectin (n = 6), a mechanism essential for proliferation, survival, and expansion of these cells. The adhesion defect of Gas6–/– erythroblasts was corrected by the addition of rGas6. (B) Survival response to Epo of WT and Gas6–/– erythroblasts adherent to fibronectin (n = 3). Apoptotic adherent erythroblasts stained by DAPI were counted as cells with nuclear fragmentation. (C) Expression of VLA4 and Ter-119 in WT (n = 9) and Gas6–/– (n = 8) spleen determined by flow cytometry. VLA4 expression is proportional to Ter-119 expression. (D) Adherence of WT versus Gas6–/– erythroblasts to fibronectin in the presence of 0.9% NaCl (vehicle), LY294002, or anti-VLA4 antibody (2 μg/106 cells) (n = 6). Values are mean ± SEM. *P < 0.05. Data were reproduced in 100% C57BL/6 background (not shown).