Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors
Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors
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DOI：
10.1073/pnas.98.3.1047
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发表时间：
2001-01-30
影响因子：
11.1
通讯作者：
Hogan, BLM
中科院分区：
文献类型：
--
作者：
Paria, BC;Ma, WG;Hogan, BLM
胚泡植入接受性子宫与一系列事件有关，即附着反应和间质蜕膜化。以往的研究证实，编码肝素结合的EGF样生长因子(HB-EGF)的基因仅在附着反应之前的囊胚贴壁部位的腔上皮细胞中表达。我们报告了21个编码其他信号蛋白的基因在植入过程中的表达，包括那些属于骨形态发生蛋白(BMP)、成纤维细胞生长因子(FGF)、WNT和Hedgehog(HH)途径的基因。我们发现，附着反应与编码BMP-2、FGF-2和WNT-4的基因的局部基质诱导有关。尽管许多研究人员做出了努力，但还没有一个简单的体外植入模型来研究胚胎在子宫中触发的事件的层级或单个信号蛋白的功能。因此，我们通过将装有纯化因子的珠子引入接受性子宫来解决这些问题。我们发现，浸泡在HB-EGF或胰岛素样生长因子-1(IG F-L)中的珠子，而不是其他蛋白质，可以引起许多与胚泡相同的离散局部反应，包括增加局部血管通透性，蜕膜化，以及珠子部位BMP2的表达。相比之下，印度刺猬(IHH)、Patted和noggin的表达结构域随着蜕膜化的进行而受到限制。值得注意的是，含有BMP-2的微珠本身不会引起植入反应，但会影响与微珠共转移的胚泡诱导的植入部位的间距。
The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone morphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgehog (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Despite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling proteins. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IG F-l), but not other proteins, induce many of the same discrete local responses elicited by the blastocyst, including increased localized vascular permeability, decidualization, and expression of Bmp2 at the sites of the beads. By contrast, the expression domains of Indian hedgehog (Ihh), patched, and noggin become restricted as decidualization proceeds. Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads.