Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment
Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment
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DOI：
10.1182/blood-2006-02-001560
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发表时间：
2006-09-15
期刊：
影响因子：
20.3
通讯作者：
Williams, David A.
中科院分区：
文献类型：
--
作者：
Ghiaur, Gabriel;Lee, Andrew;Williams, David A.
ras相关的Rho gtpase调节肌动蛋白细胞骨架组织、粘附、基因转录和细胞周期进程。Rho GTIPases和Cdc42的Rac亚家族已被证明在造血干细胞（HSC）的移植和动员中发挥重要作用。在这里，我们研究了RhoA，一个相关的Rho GTPase，在HSC功能中的作用。利用逆转录病毒介导的RhoA显性阴性（DN）突变体（RhoAN19）的基因转移，我们通过竞争性再种群和系列移植试验证明，RhoA活性的下调导致HSC植入和自我更新增加。然而，RhoAN119的过表达导致体外造血祖细胞向SDF-1 α和α (4) β(1)-和α (5) β(2)-整合素介导的粘附迁移减少。低RhoA活性与造血祖细胞的高增殖率和细胞周期活跃期的细胞增加有关，可能是通过降低p21Cip/Waf表达和增加cyclin D1水平。因此，通过优化粘附/迁移和增殖/自我更新之间的平衡来降低RhoA活性会导致HSC植入的净增加。该机制可为强化HSC治疗提供新的治疗靶点。
Ras-related Rho GTPases regulate actin cytoskeletal organization, adhesion, gene transcription, and cell-cycle progression. The Rac subfamily of Rho GTIPases and Cdc42 has been shown to play essential roles in hernatopoletic 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 RhoAN119 resulted in decreased migration toward SDF-1 alpha and alpha(4)beta(1)- and alpha(5)beta(2)-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.