SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade

• Published in: Blood Vol. 108; no. 12; pp. 3928 - 3937
• Main Authors: Pello, Oscar M., del Carmen Moreno-Ortiz, María, Rodríguez-Frade, José Miguel, Martínez-Muñoz, Laura, Lucas, Daniel, Gómez, Lucio, Lucas, Pilar, Samper, Enrique, Aracil, Miguel, Martínez-A, Carlos, Bernad, Antonio, Mellado, Mario
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.12.2006; The Americain Society of Hematology
• Subjects: Animals; Antigens, Differentiation - biosynthesis; Biological and medical sciences; Bone Marrow - metabolism; Bone Marrow Transplantation; Cattle; Cell Line; Cell Movement - genetics; Chemokine CXCL12; Chemokines, CXC - metabolism; Growth Hormone - genetics; Growth Hormone - metabolism; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic Stem Cells - metabolism; Humans; Medical sciences; Mice; Mice, Transgenic; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Suppressor of Cytokine Signaling Proteins - biosynthesis; Suppressor of Cytokine Signaling Proteins - genetics; Transplantation, Autologous; Up-Regulation; Autograft; Hematology; Stem cell; Suppressor cytokine signaling; Hematopoietic cell; Graft; Chemokine receptor; CXC chemokine; CXCR4 chemokine receptor; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-02-006353

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.