Estrogen receptor alpha regulates uterine epithelial lineage specification and homeostasis.

Postnatal development of the uterus involves specification of undifferentiated epithelium into uterine-type epithelium. That specification is regulated by stromal-epithelial interactions as well as intrinsic cell-specific transcription factors and gene regulatory networks. This study utilized mouse genetic models of deletion, endometrial epithelial organoids (EEO), and organoid-stromal co-cultures to decipher the role of in uterine epithelial development. Organoids derived from wild-type (WT) mice developed a normal single layer of columnar epithelium. In contrast, EEO from null mice developed a multilayered stratified squamous type of epithelium with basal cells. Co-culturing null epithelium with WT uterine stromal fibroblasts inhibited basal cell development. Of note, estrogen treatment of EEO-stromal co-cultures and conditional knockout mice increased basal epithelial cell markers. Collectively, these findings suggest that regulates uterine epithelium lineage plasticity and homeostasis and loss of ESR1 promotes altered luminal-to-basal differentiation driven by ESR1-mediated paracrine factors from the stroma.