Role of stroma in oestrogen-induced epithelial proliferation

To examine the role of stromal-epithelial interactions in the response of epithelial cells to oestrogens, tissue recombinations were prepared with epithelium (E) and stroma (S) from the vagina (V) and urinary bladder (BL), that is between oestrogen target tissues (VS and VE) and non-target tissues (BLS and BLE). Following 3 weeks of growth in intact female hosts, ovariectomy was performed and 1 week later the hosts subjected to various hormonal treatments. Whereas homotypic vaginal tissue recombinations (VS+VE) exhibited epithelial cornification and mucification (cycling), this activity was not observed in homotypic bladder recombinants (BLS+BLE) or in heterotypic tissue recombinants between vaginal and bladder tissues (VS+BLE and BLS+VE). In BLS+VE recombinants the epithelium remained atrophic and failed to respond to exogenous oestrogen alone or in combination with progesterone. This lack of hormonal responsiveness of vaginal epithelium was completely reconstituted when the epithelium of BLS+VE recombinants was recovered and reassociated with fresh vaginal stroma (VS). Examination of epithelial proliferative activity ([3H]thymidine labelling index) demonstrated a marked oestrogen-induced increase in epithelial proliferation in VS+VE recombinants. BLS+BLE recombinants were unresponsive to oestrogen as were recombinants composed of BLS+VE. However, when bladder epithelium was grown in association with vaginal stroma (VS+BLE) the epithelium exhibited an 8-fold oestrogen-induced increase in labelling index over oil-treated specimens. The lack of an oestrogen-induced proliferative response of vaginal epithelium in BLS+VE recombinants was reversed when the vaginal epithelium of these recombinants was recovered and reassociated with fresh vaginal stroma. These results indicate that the effects of oestrogen and progesterone on both epithelial differentiation and proliferation are critically dependent upon the appropriate stromal environment.