RESUMEN
BACKGROUND: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have demonstrated efficacy in repairing uterine scars, although the underlying mechanisms remain unclear. METHODS: Uterine injury was surgically induced in a rat model, followed by immediate transplantation of 5 × 10 ^ 5 hUC-MSCs to each side of the uterus. Uterine morphology was evaluated at days 14 and 30 using HE and Masson staining. Immunohistochemistry assessed macrophage polarization, angiogenesis and endometrial receptivity in the endometrium. Additionally, the regulatory effects of hUC-MSCs on macrophage polarization were explored through coculture. qRT-PCR quantified the expression of anti-inflammatory (IL10 and Arg1) and pro-inflammatory (iNOS and TNF-α) factors. Western blotting evaluated CD163 expression. RESULTS: Transplantation of hUC-MSCs promoted the healing of uterine injuries and tissue regeneration while inhibiting tissue fibrosis. Immunohistochemistry at days 14 and 30 post-transplantation demonstrated the polarization of macrophages toward the M2 phenotype in the uterine injury area in the presence of hUC-MSCs. Furthermore, hUC-MSC transplantation improved angiogenesis and endometrial receptivity in the uterine injury rat model, associated with increased IL10 expression. hUC-MSC-induced angiogenesis can be resisted by depleted macrophages. In vitro coculture experiments further demonstrated that hUC-MSCs promoted IL10 expression in macrophages while suppressing TNF-α and iNOS expression. Western blotting showed enhanced CD163 expression in macrophages following hUC-MSC treatment. CONCLUSIONS: hUC-MSCs contribute to the healing of uterine injuries by targeting macrophages to promote angiogenesis and the expression of anti-inflammatory factors.
RESUMEN
BACKGROUND: Chemotherapy exposure has become a main cause of premature ovarian insufficiency (POI). This study aimed to evaluate the role and molecular mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hUMSC-Exos) in ovarian function protection after chemotherapy. METHODS: hUMSC-Exos were applied to cyclophosphamide-induced premature ovarian insufficiency mice and human ovarian granulosa tumor cells (KGN) to determine their effects on follicular development and granulosa cell apoptosis. Evaluation was done for iron ion and reactive oxygen species (ROS) production, lipid peroxidation levels, and changes in iron death-related molecules (nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Glutathione Peroxidase enzyme 4 (GPX4), and Solute carrier family 7 member 11 cystine glutamate transporter (SLC7A11; xCT)). Furthermore, rescue experiments using an Nrf2 inhibitor were performed to assess the therapeutic effects of hUMSC-Exos on granulosa cells. RESULTS: hUMSC-Exos promoted ovarian hormone levels and primary follicle development in POI mice and reduced granulosa cell apoptosis. After hUMSC-Exos treatment, the ROS production, free iron ions and lipid peroxidation levels of granulosa cells decreased, and the iron death marker proteins Nrf2, xCT and GPX4 also decreased. Furthermore, the Nrf2 inhibitor ML385 significantly attenuated the effects of hUMSC-Exos on granulosa cells. CONCLUSION: hUMSC-Exos inhibit ferroptosis and protect against CTX-induced ovarian damage and granulosa cell apoptosis through the Nrf2/GPX4 signaling pathway, revealing a novel mechanism of hUMSC-Exos in POI therapy.
