Ovarian function is required for functional recovery of muscle by human ESC-derived mesenchymal progenitor cells in postmenopausal sarcopenic mice

BACKGROUND: In postmenopausal women, ovarian function decreases rapidly and is accompanied by senescence-related changes in skeletal muscle. Administration of human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs) influenced the functional maintenance of perimenopausal ovaries in female mice. MATERIALS AND METHODS: To analyze ovarian function in relation to muscle recovery using hESC-MPCs in mice with chemotherapy-induced sarcopenia, ovariectomized (OVX) and non-OVX mice were administered cisplatin. hESC-MPCs were subcutaneously transplanted into cisplatin-induced sarcopenic mice, and muscle mass and regeneration of the mice, collagen density, and transcriptomic changes were analyzed 4 weeks after transplantation in the cisplatin-only (Cis), cisplatin-MPC injection (Cis-MPC), ovariectomy and cisplatin-only (OVX-Cis), and ovariectomy and cisplatin-MPC injection (OVX-Cis-MPC) groups. In addition, the recovery of muscle cells from OVX mice was analyzed after the introduction of estradiol (E₂) or ovarian cells. RESULTS: Muscle mass was recovered in the Cis-MPC group than in the Cis group. However, in OVX mice, the therapeutic effects of hESC-MPCs were not observed in either group. The number of activated muscle stem cells was higher in the Cis-MPC group, whereas not increased in the OVX-Cis-MPC group. Bulk RNA sequencing further revealed that hESC-MPC transplantation induced transcriptional remodeling of the immune system and skeletal muscle development in sarcopenic muscles; however, this response was largely attenuated in OVX mice. In contrast, muscle function was restored when E₂ or ovarian cells were co-introduced with hESC-MPCs. CONCLUSIONS: Maintenance of ovarian function was required for hESC-MPC-mediated recovery of damaged muscles in a postmenopausal mouse model via transcriptional remodeling associated with muscle regeneration.