KERATINOCYTE GROWTH-FACTOR INJECTED INTO FEMALE MOUSE NEONATES STIMULATES UTERINE AND VAGINAL EPITHELIAL GROWTH

Estradiol (E-2,) stimulates epithelial growth in the female genital tr act via estrogen receptors (ER) in the stroma using paracrine mechanis ms. Keratinocyte growth factor (KGF), a member of the fibroblast growt h factor family, is produced by mesenchymal cells and is mitogenic for epithelial cells making it a strong candidate as a paracrine mediator . Transcripts for KGF and the KGF receptor were detected in the neonat al mouse uterus and vagina. Treatment of neonatal mice with KGF elicit ed changes in uterine and vaginal epithelium within five days and indu ced long term effects in these tissues. Newborn female Balb/c mice mer e injected daily with 5 mu g/g body weight of KGF or saline for five d ays. KGF-treated mice exhibited a 5- to 6-fold increase in uterine epi thelial BrdU-labeling index and a 4- and 5-fold increase in vaginal ep ithelial BrdU-labeling index vs. respective saline-treated controls. H istological sections of KGF-treated uteri revealed dramatic increases in epithelial surface area due to extensive folding of the luminal epi thelium. In some areas, the evaginated luminal epithelium invaded zone s normally occupied by myometrium. Vaginal epithelium was thicker than that of saline-treated controls following 5 days of KGF treatment. Wh en KGF-treated newborn mice grew to adulthood and were ovariectomized, vaginal smears exhibited persistent diestrus in all animals. Histolog ic analysis demonstrated a thick parakeratotic vaginal epithelium (sim ilar to 10 cell layers) 9 days postovariectomy in adult neonatally KGF -treated mice. Our studies indicate that KGF injected into neonates ma rkedly stimulated proliferation of neonatal uterine and vaginal epithe lium and elicited long-term, persistent abnormal changes in vaginal ep ithelium.