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Blood, 15 September 2006, Vol. 108, No. 6, pp. 2087-2094.
Prepublished online as a Blood First Edition Paper on May 18, 2006; DOI 10.1182/blood-2006-02-001560.
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STEM CELLS IN HEMATOLOGY
Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment
Gabriel Ghiaur,
Andrew Lee,
Jeff Bailey,
Jose A. Cancelas,
Yi Zheng, and
David A. Williams
From the Division of Experimental Hematology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine; the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine; the Molecular and Developmental Biology Graduate Program, University of Cincinnati; and the Hoxworth Blood Center, University of Cincinnati College of Medicine, OH.
Ras-related Rho GTPases regulate actin cytoskeletal organization, adhesion, gene transcription, and cell-cycle progression. The Rac subfamily of Rho GTPases and Cdc42 has been shown to play essential roles in hematopoietic stem cell (HSC) engraftment and mobilization. Here, we study the role of RhoA, a related Rho GTPase, in HSC functions. Using retrovirus-mediated gene transfer of a dominant-negative (DN) mutant of RhoA (RhoAN19), we demonstrate that down-regulation of RhoA activity resulted in increased HSC engraftment and self-renewal as measured by competitive repopulation and serial transplantation assays. However, overexpression of RhoAN19 resulted in decreased migration toward SDF-1 and 4 1- and 52-integrin–mediated adhesion of hematopoietic progenitor cells in vitro. Low RhoA activity was associated with higher proliferation rate of hematopoietic progenitor cells and increased cells in active phases of cell cycle, most likely via decreasing p21Cip/Waf expression and increasing cyclin D1 levels. Thus, reducing RhoA activity by optimizing the balance between adhesion/migration and proliferation/self-renewal results in a net increase in HSC engraftment. This mechanism could provide a novel therapeutic target to enhance HSC therapies.
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