SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade

The chemokine CXCL12 influences self-renewal and differentiation of hematopoietic stem cell precursors in bone marrow by directing them toward specific stromalcell components. CXCL12 up-regulates members of the SOCS family through JAK/STAT activation, a mechanism that attenuates chemokine responses. SOCS expression may thus modulate retention of hematopoietic precursors (Sca-1(+) c-Kit(+)Lin(-) cells) in bone marrow. We show that in bovine growth hormone transgenic mice and in growth hormone-treated mice, SOCS up-regulation correlated with a large number of Sca-1(+) c-Kit(+)Lin(-) cells in blood. Retroviral transduction of SOCSs blocked in vitro migration of Sca-1(+)c-Kit(+)Lin(-) cells, as well as their capacity to reconstitute lethally irradiated mice. Furthermore, in lethally irradiated mice reconstituted with bone marrow infected by a tetracycline-regulated, SOCS-expressing lentiviral vector, doxycycline treatment promoted rapid, extensive precursor mobilization to the periphery. The results indicate that by blocking CXCR4-mediated functions, SOCSs modulate hematopoietic precursor cell retention in bone marrow, and suggest the therapeutic interest of SOCS manipulation in several pathologic situations.