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

Abstract

Objectives Currently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence. Materials and methods In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function. Results The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow. Conclusions Multiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.

Preservation of ovarian function using human pluripotent stem cell-derived mesenchymal progenitor cells

“…Notably, long-term treatment with hESC-MPCs decreased the population of myeloid-derived suppressor cells (MDSCs), which increase with age and play a pivotal role in tissue fibrosis. This inhibitory effect on MDSC proliferation was further confirmed through in vitro co-culture of MDSCs with hESC-MPCs [50]. While the precise mechanisms by which hESC-MPCs inhibit MDSC proliferation and delay ovarian aging require further investigation, the results suggest that hESC-MPCs could play a key role in combating ovarian and biological aging.…”

“…Human MPCs derived from various sources, including adult tissues, fetal tissues, and PSCs, have been proposed as novel therapeutic agents for treating a range of diseases, such as reproductive senescence. In this review article, we discuss how hESC-MPCs may help preserve ovarian function (Table 1) and delay reproductive senescence in both chemotherapy-induced and naturally aging perimenopausal female mice [34,50,51]. Furthermore, a previous study indicated that the secretome of hESC-MPCs could prevent ovarian dehttps://doi.org/10.5653/cerm.2024.07003 generation and help maintain female fecundity when these cells were locally administered in a chemotherapy-induced mouse model [42].…”

“…Recent studies have reported that various substances secreted by hPSC-MPCs and adult tissue-derived MPCs play key roles in suppressing ovarian and biological aging by preventing inflammation and fibrosis (Tables 1 and 2) [34,42,[50][51][52][53][54][55][56][57][58][59]. Therefore, defining their functions and uncovering their precise mechanisms could greatly contribute to the advancement of regenerative medicine, which seeks to treat aging-related diseases in various organs, as well as to the field of reproductive medicine.…”