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.
Pello
Oscar M
OM
Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, E-28049, Madrid, Spain.
Moreno-Ortiz
María del Carmen
Mdel C
Rodríguez-Frade
José Miguel
JM
Martínez-Muñoz
Laura
L
Lucas
Daniel
D
Gómez
Lucio
L
Lucas
Pilar
P
Samper
Enrique
E
Aracil
Miguel
M
Martínez
Carlos
C
Bernad
Antonio
A
Mellado
Mario
M
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000235:genetics; D014182:Transplantation, Autologous; D015854:Up-Regulation
D000943:Antigens, Differentiation; C515255:CXCL12 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D050826:Suppressor of Cytokine Signaling Proteins; D013006:Growth Hormone