CD34⁺KLF4⁺ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair

The regenerative capacity of the human endometrium requires a population of local stem cells. However, the phenotypes, locations, and origin of these cells are still unknown. In a mouse menstruation model, uterine stromal SM22α⁺-derived CD34⁺KLF4⁺ stem cells are activated and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium; this process is correlated with enhanced protein SUMOylation in CD34⁺KLF4⁺ cells. Mice with a stromal SM22α-specific SENP1 deletion (SENP1smKO) exhibit accelerated endometrial repair in the regeneration model and develop spontaneous uterine hyperplasia. Mechanistic studies suggest that SENP1 deletion induces SUMOylation of ERα, which augments ERα transcriptional activity and proliferative signaling in SM22α⁺CD34⁺KLF4⁺ cells. These cells then transdifferentiate to the endometrial epithelium. Our study reveals that CD34⁺KLF4⁺ stromal-resident stem cells directly contribute to endometrial regeneration, which is regulated through SENP1-mediated ERα suppression.