ER71/ETV2 Is Essential for Hematopoietic Regeneration after Injury

Hematopoietic stem and progenitor cell (HSPC) expansion and regeneration is requisite for effective hematopoietic transplantation and recovery from anticancer chemotherapy drug induced bone marrow injury. In chemotherapy-mediated hematopoietic injury model, we found that key developmental genes that are critical for HSPC generation were upregulated in HSPCs when treated with 5-FU. ETS transcription factor Er71/ETV2 is essential for the development of endothelial and blood cells during mammalian embryogenesis. Here, we generated different tissue specific Er71 conditional knockout (CKO) mice as well as transgenic mice that coexpress Er71, GATA2 and Scl (EGS) in a doxycycline inducible manner to investigate the Er71 role in adult hematopoiesis. While Vav-Cre; Er71 CKO and Tie2-Cre; Er71 CKO mice did not display any hematopoietic defects in homeostatic conditions, Vav-Cre; Er71 CKO bone marrow was significantly compromised in hematopoietic reconstitution potential compared to controls.  In addition, Vav-Cre; Er71 CKO and Tie2-Cre; Er71 CKO but not VECadherin-Cre; Er71 CKO mice showed reduced HSPC proliferation and deficient HSPC and myeloid cell recovery after 5-FU injury. On the other hand, temporal Er71, GATA2 and Scl (EGS) coexpression promoted HSPC proliferation, hematopoietic reconstitution potential and regeneration after 5-FU injury. These results demonstrate that hematopoietic Er71 is critical for HSPC expansion and regeneration. Future studies warrant Er71 application for in vitro hematopoietic stem cell expansion and bone marrow regeneration in response to hematopoietic injury.