Blood, 1 December 2006, Vol. 108, No. 12, pp. 3928-3937.
Prepublished online as a Blood First Edition Paper on August 15, 2006; DOI 10.1182/blood-2006-02-006353.
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STEM CELLS IN HEMATOLOGY
SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade
Oscar M. Pello,
María del Carmen Moreno-Ortiz,
José Miguel Rodríguez-Frade,
Laura Martínez-Muñoz,
Daniel Lucas,
Lucio Gómez,
Pilar Lucas,
Enrique Samper,
Miguel Aracil,
Carlos Martínez-A,
Antonio Bernad, and
Mario Mellado
From the Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
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.
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