Endometrial Axin2⁺ Cells Drive Epithelial Homeostasis, Regeneration, and Cancer following Oncogenic Transformation

The remarkable regenerative capacity of the endometrium (the inner lining of the uterus) is essential for the sustenance of mammalian life. Over the years, the role of stem cells in endometrial functions and their pathologies has been suggested; however, the identity and location of such stem cells remain unclear. Here, we used in vivo lineage tracing to show that endometrial epithelium self-renews during development, growth, and regeneration and identified Axin2, a classical Wnt reporter gene, as a marker of long-lived bipotent epithelial progenitors that reside in endometrial glands. Axin2-expressing cells are responsible for epithelial regeneration in vivo and for endometrial organoid development in vitro. Ablation of Axin2⁺ cells severely impairs endometrial homeostasis and compromises its regeneration. More important, upon oncogenic transformation, these cells can lead to endometrial cancer. These findings provide valuable insights into the cellular basis of endometrial functions and diseases.