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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.
 Previous Article | Next Article 
Submitted February 3, 2006
Accepted April 30, 2006
Inhibition of RhoA GTPase activity enhances
hematopoietic stem and progenitor cell proliferation and
engraftment in vivo
Gabriel Ghiaur, Andrew Lee, Jeff Bailey, Jose Cancelas, Yi Zheng, and David A Williams*
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center
* Corresponding author; email: david.williams{at}cchmc.org.
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 transfere of 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, over expression
of RhoAN19 resulted in decreased migration toward SDF-
1 and 4 1- /51-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 cyclinD1 levels. Thus, reducing RhoA activity
by optimizing the balance between adhesion/migration and
proliferation/self-renewal results in a net increased in
HSC engraftment. This mechanism could provide a novel
therapeutic target to enhance HSC therapies.
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