Olfactomedin4 marks luminal progenitor cells that give rise to secretory cell lineage in the mouse cervix

SUMMARY Development of the female reproductive tract in mice occurs in early postnatal life. The current model identifies Trp63 as the master regulator that initiates differentiation of simple columnar Keratin 8+ epithelium in the cervix and vagina into a stratified squamous epithelium. Thereafter Trp63+ basal progenitors maintain cervicovaginal epithelial cell homeostasis and in the adult serve as the progenitor for hormone-regulated shifts in stratified squamous and secretory luminal cells. This model differs from the human in which two progenitors, one columnar and the other basal gives rise to secretory cells in the endocervix and stratified squamous epithelia in the ectocervix and vagina respectively. In the current study, we identify a population of Krt8+, Tp63- epithelial cells that are retained in the cervicovaginal epithelium during the postnatal developmental period and into adulthood. Single cell datasets from the cervices of adult mice, identify Olfactomedin 4 (Olfm4), as a unique marker of the Krt8+Trp63- population. Adult lineage tracing and reassessment of gene markers during postnatal development support a revised model in which two progenitors are delineated in the mouse cervix and vagina by PND15. Olfactomedin 4+ progenitors give rise to specialized secretory goblet cells, while Trp63+ basal progenitors give rise to stratified squamous luminal cells in the cervix and vagina of nonpregnant and pregnant mice. Consistent with the expansion of goblet cells in pregnancy, the Olfm4+ progenitor is highly proliferative in early pregnancy and progesterone regulates increased goblet cell differentiation. These findings reveal a previously unrecognized species similarity between mice and humans in which goblet cell and squamous keratinized cell subtypes are derived from two progenitor populations respectively. HIGHLIGHTS Two epithelial progenitors (Trp63 and Olfm4) populations are delineated in the cervix and vagina within the first two weeks of postnatal life. The Trp63+ progenitor gives rise to keratinized epithelial cells, whereas the Olfm4+ progenitor cells give rise to secretory goblet cells. lfm4 is not required for maintenance of the luminal progenitor or differentiation of goblet cells in the cervix and vagina during adulthood and pregnancy. In adults, progesterone promotes differentiation of Olfm4+ progenitors into goblet cells. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵^ Lead contact