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Role of Stromal and Epithelial Estrogen Receptors in Vaginal Epithelial Proliferation, Stratification, and Cornification¹

Department of Veterinary Biosciences (D.L.B., P.S.C.), University of Illinois, Urbana, Illinois 61802; Department of Anatomy (T.K., G.R.C.), University of California, San Francisco, California 94143; and Departments of Biochemistry and Child Health (J.A.T., D.B.L.), University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: Paul Cooke, Department of Veterinary Biosciences, University of Illinois, 2001 South Lincoln Avenue, Urbana, Illinois 61802.

Estradiol 17-ß (E₂) induces epithelial proliferation, stratification, and cornification in vaginal epithelium. Our aim was to determine the respective roles of epithelial and stromal estrogen receptor- (ER) in these E₂-induced events. Vaginal epithelium (E) and stroma (S) from adult ER knockout (ko) and wild-type (wt) neonatal Balb/c mice were enzymatically separated and used to produce four types of tissue recombinants in which epithelium, stroma, or both lack functional ER. Tissue recombinants were grafted into female nude mice, which were subsequently ovariectomized and treated with oil or E₂. In response to E₂ treatment, grafts prepared with wt-S (wt-S + wt-E and wt-S + ko-E) showed similar large increases in epithelial labeling index, indicating that E₂ stimulated epithelial proliferation despite a lack of epithelial ER in wt-S + ko-E tissue recombinants. Conversely, in tissue recombinants prepared with ko-S (ko-S + wt-E and ko-S + ko-E), epithelial labeling index remained at baseline levels after E₂ or oil treatment, even though epithelial ER were detected in ko-S + wt-E grafts. Epithelial cornification was present in wt-S + wt-E grafts from E₂-treated hosts, whereas epithelium in all other tissue recombinants failed to cornify. Grafts composed of wt-S + wt-E from E₂-treated hosts had highly stratified epithelium, whereas epithelial thickness was reduced almost 60% in wt-S + ko-E tissue recombinants grown in E₂-treated hosts and was atrophic in all other tissue recombinants. In addition, cytokeratin 10, a marker of epithelial differentiation, was strongly expressed in wt-S + wt-E tissue recombinants grown in E₂-treated hosts but was markedly reduced or absent in all other tissue recombinants. These results indicate that E₂-induced vaginal epithelial proliferation is mediated indirectly through stromal ER, consistent with our recent findings in uterus. Conversely, both epithelial and stromal ER are required for E₂-induced cornification and normal epithelial stratification. These are the first known functions attributed to epithelial ER in vivo and the first time any epithelial response to E₂ has been shown to involve both stromal and epithelial ER.

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