Reproductive tissue-derived stromal cells rescue fertility by coupling follicular activation with endometrial...

Mesenchymal stromal cells (MSCs) of various origins promote regeneration through paracrine signaling, immune modulation, and angiogenesis support. Premature ovarian failure (POF) is an excellent model to study coordinated ovarian and uterine repair, as cytotoxic injury simultaneously depletes ovarian follicles and impairs uterine receptors, resulting in infertility.

We established a busulfan/cyclophosphamide (Bu/Cy) POF model and applied human MSCs derived from reproductive/perinatal tissues-endometrium (hEndSCs), menstrual blood (hMenSCs), placenta (hPSCs), or follicular fluid (hFFSCs)-to treat the condition. The primary endpoint was pregnancy rate; secondary endpoints included serum anti-Mullerian hormone (AMH) levels and ovarian/uterine molecular profiles (RT-qPCR panels; selected ovarian signaling proteins by Western blot).

Chemotherapy reduced fertility (0%) and AMH levels compared to healthy controls. MSC therapy restored fertility in 41%-75% of mice, with hEndSC and hMenSC achieving the highest pregnancy rates (both 75%) and the highest AMH recovery. In the ovary, MSC increased Amh, Gdf3, Gja1, Zp1, and, depending on the source, Fshr, with concomitant activation of PI3K/AKT/mTOR effectors (p-AKT, p-mTOR, p-GSK3β, p-PDK1). In the uterus, MSC increased the expression of Col1a1, Col3a1, Ctgf, Pcna, Ccnd1, and Ki67, consistent with extracellular matrix repair and proliferative renewal.

These data suggest that MSCs derived from reproductive tissues, particularly endometrial origin, may restore fertility in POI by linking follicular activation to endometrial remodeling and support the translational development of MSC therapies that address both follicular depletion and uterine competence in infertility.