Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium
Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium
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基质雌激素受体介导雌二醇对子宫上皮细胞的有丝分裂作用
DOI：
10.1073/pnas.94.12.6535
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发表时间：
1997-06-10
影响因子：
11.1
通讯作者：
Cunha, GR
中科院分区：
文献类型：
--
作者：
Cooke, PS;Buchanan, DL;Cunha, GR
雌二醇-17 β (E-2)通过雌激素受体（ER）调节子宫生长和功能分化。为了确定E-2是通过上皮ER诱导上皮细胞有丝分裂，还是间接通过ER阳性基质细胞诱导上皮细胞有丝分裂，我们利用成年ER缺乏ER敲除小鼠（ko）和新生ER阳性野生型（wt） BALB/c小鼠的子宫产生以下组织重组：wt-S + wt-E、wt-S + ko-E、ko-S + ko-E和ko-S + wt-E。将组织重组体作为肾下包膜移植物在完整雌性裸鼠体内培养4周，切除卵巢后1周给予E-2或油处理，分别用[H-3]胸腺嘧啶放射自显影法和免疫组化法测定上皮标记指数和ER表达。在wt-S + ko-E组织重组中，尽管上皮性ER缺失，但与油处理的对照组相比，E-2诱导两种组织重组中上皮标记指数的增加相似，这种增殖作用被ER拮抗剂阻断，表明它是通过ER介导的。相反，在ko-S制备的组织重组中（ko-S + ko-E和ko-S + wt-E）。尽管上皮ER在ko-S + wt-E移植中表达，但上皮标记指数较低且不受E-2的刺激。综上所述，这些数据表明上皮ER对于E-2诱导的子宫上皮增殖既不是必要的也不是充分的，相反，E-2诱导的上皮增殖似乎是由ER阳性基质介导的旁分泌事件。子宫的这些数据和前列腺的类似研究表明，雌激素和雄激素靶器官的上皮有丝分裂都是基质介导的事件。
Estradiol-17 beta (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 [H-3] 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.