Organoid transplantation in the adult endometrium restores fertility and uncovers epithelial lineage plasticity

The adult endometrium, which continuously regenerates itself, has cells and mechanisms for rebuilding its epithelium that are not well understood. To manage the cell types involved in regeneration, a genetic strategy was employed to extensively remove the uterine epithelium, followed by transplantation of organoids labeled with lineage markers.

While removing the epithelium without organoid transplantation led to re-epithelialization, it also resulted in infertility. However, when the researchers transplanted endometrial epithelial organoids into the ablated uterus, both the luminal and glandular epithelia were reconstructed, and fertility was restored. By removing the glandular lineage from the organoids before transplantation, it was discovered that luminal epithelial cells, derived from glands, acquire glandular identity and function after engraftment.

The same luminal-to-glandular epithelial differentiation pathway was observed during the endogenous repair process following targeted glandular ablation. These findings confirm that luminal-to-glandular epithelial conversion is an intrinsic regenerative capability of the adult uterine epithelium and establish an endometrial organoid transplantation platform with potential therapeutic applications.