CXCR7 participates in CXCL12-induced CD34~+ cell cycling through P-arrestin-dependent Akt activation

摘要

In addition to its well-known effect on migration and homing of hematopoietic stem/ progenitor cells (HSPCs), CXCL12 chemokine also exhibits a cell cycle and survival-promoting factor for human CD34~+ HSPCs. CXCR4 was suggested to be responsible for CXCL12-induced biological effects until the recent discovery of its second receptor, CXCR7. Until now, the participation of CXCR7 in CXCL12-induced HSPC cycling and survival is unknown. We show here that CXCL12 was capable of binding CXCR7 despite its scarce expression at CD34~+ cell surface. Blocking CXCR7 inhibited CXCL12-induced Akt activation as well as the percentage of CD34~+ cells in cycle, colony formation, and survival, demonstrating its participation in CXCL12-induced functional effects in HSPCs. At steady state, CXCR7 and beta-arrestin2 co-localized near the plasma membrane of CD34~+ cells. After CXCL12 treatment, beta-arrestin2 translocated to the nucleus, and this required both CXCR7 and CXCR4. Silencing p-arrestin expression decreased CXCL12-induced Akt activation in CD34~+ cells. Our results demonstrate for the first time the role of CXCR7, in the control of HSPC cycling, survival, and colony formation induced by CXCL12. We also beta-arrestins as signaling hubs downstream of both CXCL12 receptors in primary human complementary to that played by CXCR4, provide evidence for the involvement of HSPCs.