Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma
Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma
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DOI：
10.1210/en.139.3.913
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发表时间：
1998-03-01
期刊：
影响因子：
4.8
通讯作者：
Cunha, GR
中科院分区：
文献类型：
--
作者：
Hom, YK;Young, P;Cunha, GR
雌激素对女性生殖道的生长和功能至关重要。最近，我们发现雌二醇诱导子宫上皮细胞增殖是一种旁分泌过程，需要雌激素受体阳性的基质。生长因子[如EGF（表皮生长因子）配体]可能是旁分泌介质，其可以通过细胞-细胞相互作用直接或间接调节雌激素靶器官中的上皮增殖。在这份报告中，我们使用了一个无效突变的小鼠在他们的表皮生长因子受体（EGFR），研究EGFR信号在子宫和阴道的生长和雌激素诱导的子宫和阴道上皮细胞增殖的作用。当WT和EGFR敲除（EGFR-KO）的子宫和阴道在裸鼠中作为肾包膜移植物生长时，与WT小鼠相比，EGFR-KO小鼠的子宫和阴道移植物的生长减少。EGFR-KO子宫和阴道的移植物比其相应的WT器官小约三分之一（湿重），即使在两种情况下上皮和间充质的分化都是正常的。野生型和EGFR-KO阴道移植物在其管腔内均含有皮质层和粘液化上皮细胞层的交替层，表明上皮分化的周期性改变。与WT子宫和阴道移植物中的基质细胞LI相比，EGFR-KO子宫和阴道移植物中的基质细胞标记指数（LI）对雌二醇治疗的响应（通过掺入H-3-胸苷评估）严重降低。出乎意料的是，EGFR-KO和野生型移植物的上皮细胞对雌二醇的反应均不明显，子宫和阴道上皮细胞中对雌二醇的反应使上皮细胞LI显著升高（总体相似于7倍）。这些数据支持这样的假设，即整体子宫和阴道器官的生长，在雌激素的反应，需要EGFR信号的DNA合成的纤维肌基质，而EGFR信号不是必需的雌激素诱导的上皮细胞生长在子宫和阴道。
Estrogens are crucial for growth and function of the female genital tract. Recently, we showed that induction of uterine epithelial proliferation by estradiol is a paracrine event requiring an estrogen receptor-positive stroma. Growth factors [such as EGF (epidermal growth factor) ligands] are likely paracrine mediators, which may directly or indirectly regulate epithelial proliferation in estrogen target organs via cell-cell interactions. In this report, we used mice with a null mutation in their EGF receptor (EGFR) to examine the role of EGFR signaling in growth of the uterus and vagina and in estrogen-induced uterine and vaginal epithelial proliferation. When WT and EGFR-knockout (EGFR-KO) uteri and vaginae were grown as renal capsule grafts in nude mice, growth of uterine and vaginal grafts of EGFR-KO mice was reduced, compared with their WT counterparts. Grafts of both EGFR-KO uteri and vaginae were about one third smaller (wet weight) than their corresponding WT organs, even though differentiation of both epithelium and mesenchyme were normal in both cases. Both wild-type and EGFR-KO vaginal grafts contained within their lumina alternating layers of cornified and mucified epithelial cell layers, indicating cyclic alteration of epithelial differentiation. In response to estradiol treatment, stromal cell labeling index (LI), as assessed by incorporation of H-3-thymidine, was severely depressed in EGFR-KO uterine and vaginal grafts vs. stromal cell LI in WT uterine and vaginal grafts. Unexpectedly, epithelium of both EGFR-KO and wild-type grafts responded comparably to estradiol with a marked elevation (similar to 7-fold overall) of epithelial LI in response to estradiol in uterine and vaginal epithelia. These data supported the hypothesis that overall uterine and vaginal organ growth, in response to estrogen, required EGFR signaling for DNA synthesis in the fibromuscular stroma, whereas EGFR signaling was not essential for estrogen-induced epithelial growth in the uterus and vagina.