Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration
Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration
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DOI：
10.1073/pnas.0806219105
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发表时间：
2008-10-21
影响因子：
11.1
通讯作者：
Mardon, Helen J.
中科院分区：
文献类型：
--
作者：
Grewal, Seema;Carver, Janet G.;Mardon, Helen J.
人类胚胎在怀孕早期未能植入子宫壁是不孕症的主要原因。着床涉及胚胎贴壁和粘附到子宫内膜上皮，随后穿透上皮和胚胎滋养层侵入子宫内膜基质。尽管基因敲除研究已经强调了几种对小鼠植入很重要的分子，但控制人类植入的分子机制尚不清楚。在这里，我们证明了在体外模型中的人类植入的Rho GTP酶Rac1和RhoA在人类子宫内膜间质细胞调节人类胚胎通过子宫内膜间质的入侵。我们发现，Rac1在人子宫内膜间质细胞表达的敲低抑制人胚胎滋养层细胞侵入基质细胞单层，而RhoA活性的抑制促进胚胎侵入。此外，我们证明Rac1是人类子宫内膜间质细胞迁移所必需的，并且在着床部位间质细胞的运动性增加。这种增加的运动性与Rac1激活的局部增加和RacGAP 1水平的相互降低相关。这些结果揭示了胚胎诱导的和局部的子宫内膜反应，可能支配人类胚胎的植入。
Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.