Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium

Estradiol-17β (E(2)) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether E(2) elicits epithelial mitogenesis through epithelial ER versus indirectly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and/or stroma (S), or lacking ER altogether: wt-S + wt-E, wt-S + ko-E, ko-S + ko-E, and ko-S + wt-E. Tissue recombinants were grown for 4 weeks as subrenal capsule grafts in intact female nude mice, then the hosts were treated with either E(2) or oil a week after ovariectomy. Epithelial labeling index and ER expression were determined by [(3)H]thymidine autoradiography and immunohistochemistry, respectively. In tissue recombinants containing wt-S (wt-S + wt-E, wt-S + ko-E), E(2) induced a similar large increase in epithelial labeling index compared with oil-treated controls in both types of tissue recombinants despite the absence of epithelial ER in wt-S + ko-E tissue recombinants. This proliferative effect was blocked by an ER antagonist, indicating it was mediated through ER. In contrast, in tissue recombinants prepared with ko-S (ko-S + ko-E and ko-S + wt-E), epithelial labeling index was low and not stimulated by E(2) despite epithelial ER expression in ko-S + wt-E grafts. In conclusion, these data demonstrate that epithelial ER is neither necessary nor sufficient for E(2)-induced uterine epithelial proliferation. Instead, E(2) induction of epithelial proliferation appears to be a paracrine event mediated by ER-positive stroma. These data in the uterus and similar studies in the prostate suggest that epithelial mitogenesis in both estrogen and androgen target organs are stromally mediated events.

17β-雌二醇（Estradiol-17β，E₂）通过雌激素受体（estrogen receptor，ER）调控子宫生长与功能分化。为明确E₂是通过上皮自身的ER介导上皮细胞有丝分裂增殖，还是间接经由ER阳性基质细胞实现该过程，研究人员选取成年ER敲除（ER knockout，ko）小鼠与新生ER阳性野生型（wild-type，wt）BALB/c小鼠的子宫，构建了四类组织重组体：上皮与基质均表达ER的wt-S + wt-E、基质表达ER但上皮为ko型的wt-S + ko-E、上皮与基质均不表达ER的ko-S + ko-E，以及基质为ko型但上皮表达ER的ko-S + wt-E。将上述组织重组体作为肾被膜下移植体（subrenal capsule grafts），在未去势雌性裸鼠（nude mice）体内培养4周；随后对宿主实施卵巢切除术（ovariectomy），术后一周分别给予E₂或油剂对照处理。分别通过[³H]胸腺嘧啶核苷放射自显影术（[³H]thymidine autoradiography）与免疫组织化学法（immunohistochemistry）检测上皮标记指数（epithelial labeling index）与ER表达水平。在基质表达ER的重组体（wt-S + wt-E、wt-S + ko-E）中，尽管wt-S + ko-E重组体的上皮不表达ER，但与油剂处理的对照组相比，E₂均可诱导两类重组体的上皮标记指数出现显著且相似的升高。该增殖效应可被ER拮抗剂（ER antagonist）阻断，提示其通过ER介导。与之相反，在基质为ko型的重组体（ko-S + ko-E与ko-S + wt-E）中，即便ko-S + wt-E移植体的上皮表达ER，其上皮标记指数仍处于较低水平，且未被E₂诱导升高。综上，本研究数据表明，上皮自身的ER既非E₂诱导子宫上皮增殖所必需，也不足以介导该过程。相反，E₂诱导上皮增殖似乎是由ER阳性基质细胞介导的旁分泌事件（paracrine event）。本研究在子宫中的发现与前列腺中的同类研究均提示，雌激素与雄激素靶器官（androgen target organs）中的上皮细胞有丝分裂增殖均为基质介导的过程。