Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved fertility and ovarian function of perimenopausal mice undergoing natural aging.

Abstract Objectives: There is no approved therapy to preserve ovarian health with aging. To solve this problem, we developed a long-term treatment of human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs) and investigated whether the cells retained the ability to resist ovarian aging, leading to delayed reproductive senescence. Materials and Methods: In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs have a beneficial effect on the long-term maintenance of reproductive fecundity and the ovarian reservoir or how their transplantation regulates ovarian function. Results: The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice underwent multiple introductions of hESC-MPCs compared to age-matched controls. The level of estradiol in the hESC-MPC group was similar to that of the young and adult groups. Embryonic development and live birth rate were increased in the hESC-MPC group compared with the control group, suggesting a delay in ovarian senescence by hESC-MPCs. In addition to the direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via suppression of myeloid-derived suppressor cells (MDSCs) produced in bone marrow. Conclusions: Multiple introduction of hESC-MPCs could be a useful approach to maintain ovarian function in female reproductive aging and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.