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 4

Expression of Gas6 and Gas6Rs in erythroblasts.

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Expression of Gas6 and Gas6Rs in erythroblasts. (A) Western blot analysi...
(A) Western blot analysis of Axl and Mertk in spleen erythroblasts isolated from WT, Tyro3–/–, Axl–/–, and Mertkkd mice. Equal amounts of protein cell lysates were loaded per well. (B) Erythropoiesis of Tyro3–/–, Axl–/– or Mertkkd mice in response to PHZ. Overall genotypic differences versus WT (after Dunnett’s correction for multiple testing) were as follows: Tyro3–/–, P = 0.49 (n = 18); Axl–/–, P = 0.007 (n = 9); Mertkkd, P = 0.97 (n = 5). (C) WT and Axl–/– mice were subjected to PHZ-induced hemolytic anemia (injections of a half dose of PHZ on days 0 and 1) and treated with saline or rGas6 (2 μg daily intraperitoneally). P < 0.05, Axl–/– and Axl–/– plus rGas6 versus WT; P > 0.05, Axl–/– versus Axl–/– plus rGas6.