THECAL CELL-GRANULOSA CELL-INTERACTIONS INVOLVE A POSITIVE FEEDBACK LOOP AMONG KERATINOCYTE GROWTH-FACTOR, HEPATOCYTE GROWTH-FACTOR, AND KIT-LIGAND DURING OVARIAN FOLLICULAR DEVELOPMENT

Interactions between mesenchymal-derived thecal cells and epithelial-d erived granulosa cells are essential for follicular development in the ovary. These mesenchymal-epithelial cell interactions are in part med iated by keratinocyte growth factor (KGF), hepatocyte growth factor (H GF), and Kit ligand (KL). This study investigates the hypothesis that thecal cell-derived growth factors (e.g. KGF and HGF) regulate granulo sa cell function, and granulosa cell-derived growth factors (e.g. KL) regulate thecal cell function. Gonadotropin regulation of this cell-ce ll interaction is also examined. Sensitive quantitative RT-PCR assays were used to analyze gene expression of KGF, HGF, and KZ, in the ovary . Thecal cell-derived KGF and HGF stimulated KL expression in bovine g ranulosa cells. Granulosa cell-derived KL stimulated KGF and HGF expre ssion in bovine thecal cells. These results suggest that thecal and gr anulosa cells interact in a positive feedback loop mediated by KGF, KG F, and KL. Previous studies have suggested that gonadotropins (i.e. FS H and LH) regulate locally produced growth factor expression in the ov ary. Treatment of bovine granulosa cells with FSH and hCG ia LH agonis t) directly stimulated KL expression. The LH agonist hCG was also foun d to stimulate both KGF and HGF expression in thecal cells. The action s of gonadotropins on follicular development may in part be indirectly regulated by KL, KGF, and HGF expression. A novel positive feedback l oop was identified between thecal cells and granulosa cells that is me diated by KL, KGF, and HGF. Thecal cell-derived KGF and HGF can stimul ate granulosa cell-derived KL expression, and KL, in turn, can stimula te thecal cell-derived KGF and HGF expression. Combined observations s upport the hypothesis that mesenchymal-epithelial cell interactions be tween thecal and granulosa cells can play a significant role during ov arian follicular development and mediate gonadotropin actions.