The activation function-1 domain of estrogen receptor α in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen
The activation function-1 domain of estrogen receptor α in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen
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DOI：
10.1111/j.1432-0436.2005.00033.x
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发表时间：
2005-07-01
期刊：
影响因子：
2.9
通讯作者：
Gold, LI
中科院分区：
文献类型：
--
作者：
Kurita, T;Medina, R;Gold, LI
间质细胞中雌激素受体α(ERα)的激活功能-1(AF-1)结构域被证明是小鼠子宫上皮细胞对雌激素反应所必需的。为探讨基质在人子宫上皮(HUtE)雌激素反应中的作用，将人子宫上皮与小鼠基质组成的人/鼠嵌合子宫制备成组织重组体，接种于裸鼠雌性宿主肾被膜下。HUtE与小鼠子宫间质(MutS)结合形成被小鼠子宫内膜间质包围的正常腺体，人上皮影响间质分化为肌层，从而形成组织学上看正常的子宫组织。HUtE对17β-雌二醇(E-2)的增殖反应和孕激素受体(PR)的增加与人或MutS类似。然而，在相同的内分泌和微环境条件下，hUtE需要5-7天的E-2暴露，而不是像小鼠子宫上皮那样1天，才能获得最大的增殖反应。此外，在存在小鼠基质的情况下，这种延长的E-2暴露长度抑制了小鼠上皮的增殖。此外，与小鼠上皮细胞不同，小鼠上皮细胞不会因E-2而增殖或表现出PR表达的调节，这些细胞与来自ERα的AF-1结构域缺失的小鼠子宫基质细胞相关，hUtE增殖和PR在与E-2相关的遗传相同的ERα敲除小鼠基质细胞中被上调。这些结果清楚地表明，在调节雌激素诱导的增殖和PR表达的机制方面，小鼠和人的子宫上皮细胞存在根本的差异。此外，我们表明，基因工程小鼠模型可能有助于解剖人类子宫间质上皮相互作用的分子通路。
The activation function-1 (AF-1) domain of the estrogen receptor alpha (ER alpha) in stromal cells has been shown to be required for epithelial responses to estrogen in the mouse uterus. To investigate the role of the stroma in estrogenic responses of human uterine epithelium (hUtE), human/mouse chimeric uteri composed of human epithelium and mouse stroma were prepared as tissue recombinants (TR) that were grown in vivo under the renal capsule of female nude mouse hosts. In association with mouse uterine stroma (mUtS), hUtE formed normal glands surrounded by mouse endometrial stroma and the human epithelium influenced the differentiation of stroma into myometrium, such that a histologically normal appearing uterine tissue was formed. The hUtE showed a similar proliferative response and increase in progesterone receptors (PR) in response to 17 beta-estradiol (E-2) in association with either human or mUtS, as TRs. However, under identical endocrine and micro-environmental conditions, hUtE required 5-7 days exposure to E-2 rather than 1 day, as shown for mouse uterine epithelium, to obtain a maximal proliferative response. Moreover, this extended length of E-2 exposure inhibited mouse epithelial proliferation in the presence of mouse stroma. In addition, unlike the mouse epithelium, which does not proliferate or show regulation of PR expression in response to E-2 in association with uterine stroma derived from mice that are null for the AF-1 domain of ER alpha, hUtE proliferates and PR are up-regulated in response to E-2 in association genetically identical ER alpha knock-out mouse stromal cells. These results clearly demonstrate fundamental differences between mouse and human uterine epithelia with respect to the mechanisms that regulate estrogen-induced proliferation and expression of PR. Moreover, we show that genetically engineered mouse models could potentially aid in dissecting molecular pathways of stromal epithelial interactions in the human uterus.