SMAD2/3 signaling in the uterine epithelium controls endometrial cell homeostasis and regeneration

Abstract The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids were used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre developed endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determined that genetic or pharmacological inhibition of SMAD2/3 signaling disrupted organoid morphology, increased the glandular and secretory cell markers, FOXA2 and MUC1, and altered the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids revealed elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFβ family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.