GROWTH-FACTOR CONTROL OF CULTURED RAT UTERINE STROMAL CELL-PROLIFERATION IS PROGESTERONE-DEPENDENT

Uterine stromal cells undergo mitosis and differentiate into the decid ua just prior to the expected time of implantation in humans and roden ts. We have utilized a culture system that will be suitable for study of the molecular mechanisms regulating stromal cell proliferation. Str omal cells were isolated from the uteri of ovariectomized rats and wer e cultured in chemically defined medium. Cultured cells express the me senchymal markers vimentin and desmin. They do not express the epithel ial marker cytokeratin. Serum-starved stromal cells were stimulated to proliferate in a time frame consistent with the cell cycle through ad dition of a panel of growth factors (basic fibroblast growth factor [b FGF], epidermal growth factor, platelet-derived growth factor, transfo rming growth factor or, insulin-like growth factor I) and hormones to the culture medium. None of the growth factors tested significantly st imulated proliferation in the absence of progesterone. Furthermore, pr ogesterone was the only steroid of those tested that stimulated mitosi s in the presence of growth factors. Stromal cell proliferation in res ponse to progesterone and bFGF was dose dependent and saturable. Addit ion of the progesterone receptor antagonist mifepristone (RU 486) and an inhibitor of tyrosine kinase receptor activation (suramin) abolishe d stromal cell mitosis. Progesterone receptors and fibroblast growth f actor receptor 1 (FGFR1) were identified by immunoblot analysis in pro liferating stromal cells. Taken together, these results show that cult ured stromal cells maintain progesterone-dependent cell cycle control that is mediated via progesterone receptors. Moreover, the data indica te that bFGF control of stromal cell proliferation is modulated via a specific isoform of FGFR1 containing the three-loop immunoglobulin-lik e domain.