Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment
- 15 September 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 108 (6), 2087-2094
- https://doi.org/10.1182/blood-2006-02-001560
Abstract
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-1α and α4β1- and α5β2-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.Keywords
This publication has 53 references indexed in Scilit:
- Hematopoietic Cell Regulation by Rac1 and Rac2 Guanosine TriphosphatasesScience, 2003
- Identification of the haematopoietic stem cell niche and control of the niche sizeNature, 2003
- Augmentation of umbilical cord blood (UCB) transplantation with ex vivo–expanded UCB cells: results of a phase 1 trial using the AastromReplicell SystemBlood, 2003
- Stem Cell MobilizationHematology-American Society Hematology Education Program, 2003
- Influence of multiplicity of infection and protein stability on retroviral vector-mediated gene expression in hematopoietic cellsGene Therapy, 2001
- G Proteins and Small GTPases: Distant Relatives Keep in TouchScience, 1998
- The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral BloodThe Journal of Experimental Medicine, 1997
- Differentiation of primitive human multipotent hematopoietic progenitors into single lineage clonogenic progenitors is accompanied by alterations in their interaction with fibronectin.The Journal of Experimental Medicine, 1991
- The hematopoietic microenvironmentCritical Reviews in Oncology/Hematology, 1991
- The Distribution of Haemopoietic Colony-Forming Units in the Mouse Femur, and its Modification by X RaysThe British Journal of Radiology, 1972