Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization
Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization
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DOI：
10.1038/nm1274
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发表时间：
2005-08-01
期刊：
影响因子：
82.9
通讯作者：
Williams, DA
中科院分区：
文献类型：
--
作者：
Cancelas, JA;Lee, AW;Williams, DA
调节造血干细胞和祖细胞（HSC/Ps）的植入和动员的分子事件仍然不完全确定（1，2）。我们研究了Rho GTP酶Rac 1和Rac 2在HSC植入和动员中的作用。造血重建的植入阶段需要Rac 1，而不是造血特异性Rac 2，因为Rac 1（-/-）HSC在移植后不能挽救体内造血，但植入后Rac 1的缺失不会损害稳态造血。Rac 1（-/-）HSC/Ps在体内表现出骨内膜的空间定位受损，但接近正常的髓腔归巢。在体外与骨髓微环境的相互作用显着改变。而Rac 1单独的移植后缺失并不损害造血，Rac 1和Rac 2的缺乏导致造血干细胞从骨髓中大量动员，与无效的造血和对表达Rac的造血干细胞的强烈选择相关。这种动员是可逆的Rac 1的重新表达。此外，一个合理设计的，可逆的小分子抑制剂的Rac激活导致瞬时动员可移植的HSC/Ps。因此，Rac蛋白差异性地调节植入和动员表型，这表明这些生物过程和稳态造血是生物化学上可分离的，并且Rac蛋白可能是干细胞修饰的重要分子靶点。
The molecular events that regulate engraftment and mobilization of hematopoietic stem cells and progenitors (HSC/Ps) are still incompletely defined(1,2). We have examined the role of the Rho GTPases Rac1 and Rac2 in HSC engraftment and mobilization. Rac1, but not the hematopoietic-specific Rac2, is required for the engraftment phase of hematopoietic reconstitution, because Rac1(-/-) HSCs did not rescue in vivo hematopoiesis after transplantation, but deletion of Rac1 after engraftment did not impair steady-state hematopoiesis. Rac1(-/-) HSC/Ps showed impaired spatial localization to the endosteum but near-normal homing to the medullary cavity in vivo. Interaction with the bone marrow microenvironment in vitro was markedly altered. Whereas post-engraftment deletion of Rac1 alone did not impair hematopoiesis, deficiency of both Rac1 and Rac2 led to massive mobilization of HSCs from the marrow associated with ineffective hematopoiesis and intense selection for Rac-expressing HSCs. This mobilization was reversible by re-expression of Rac1. In addition, a rationally designed, reversible small-molecule inhibitor of Rac activation led to transient mobilization of engraftable HSC/Ps. Rac proteins thus differentially regulate engraftment and mobilization phenotypes, suggesting that these biological processes and steady-state hematopoiesis are biochemically separable and that Rac proteins may be important molecular targets for stem cell modification.