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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 Article has an altmetric score of 26

Role of Gas6 in erythropoiesis and anemia in mice

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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 3

Erythropoietic response to acute anemia in WT (black lines) and Gas6–/– (red lines) mice.

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Erythropoietic response to acute anemia in WT (black lines) and Gas6–/– ...
P values above the graphs denote overall genotypic difference during the entire period of analysis, as analyzed by ANOVA for repeated measurement statistics. *P < 0.05, standard t test. (A–D) Impaired erythropoiesis in Gas6–/– compared with WT mice in response to PHZ-induced hemolytic anemia. (A and B) Hematocrit levels (A) and reticulocyte indices (B) after 2 PHZ injections on days 0 and 1 (n = 8). Data were reproduced in 100% C57BL/6 background (Supplemental Figure 1). (C and D) Impaired erythropoiesis in Gas6–/– mice in response to autoimmune hemolytic anemia, induced by intraperitoneal injection of the 34-3C anti-mouse rbc monoclonal antibody (200 μg on day 0). (C) Hematocrit levels. (D) Reticulocyte indices (n = 8). (E) Impaired erythropoiesis in Gas6–/– splenectomized mice in response to injections of PHZ injections on days 0 and 1 (n = 6). (F) Hematocrit levels in Gas6–/– and WT mice after PHZ injections on days 0, 1 and 2 (n = 6). A hematocrit value of 11% (the lowest detectable hematocrit level in preterminal mice) was assigned to the mice that died in the course of the experiment. Values are mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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