Secretome Derived from Estrogen Receptor-Expressing Human Placenta-Derived Mesenchymal Stem Cells Restores Ovarian Function and Circadian Rhythm in Mice with Cyclophosphamide-Induced Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is characterized by an early decline in ovarian function in reproductive-aged women, leading to infertility. While cancer chemotherapy is a common cause of POI, current treatments for chemotherapy-induced POI remain largely ineffective. Recently, mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option for POI. However, the mechanisms of the MSC secretome on ovarian regeneration and circadian rhythm, particularly in relation to the ovarian estrogenic environment, are still unclear.
This study investigates the therapeutic potential of the secretome derived from estrogen receptor-positive human placenta mesenchymal stem cells (ER+pcMSCs). The findings demonstrate that the secretome from ER+pcMSCs, either with or without estradiol (E2) priming (CM/E2-CM), significantly improves ovarian folliculogenesis and addresses circadian rhythm disruptions induced by cyclophosphamide (CTX). Furthermore, the secretome was found to reduce apoptosis in ovarian granulosa cells, promote angiogenesis in POI-affected ovarian tissues, and restore the expression of key ovarian circadian clock genes, including Rora, E4bp4, Rev-erb, and Dbp.
Additionally, miRNAs contained in the pcMSC-CM exosomes were identified as targeting critical pathways. These included miRNAs regulating apoptosis via caspase-3 (hsa-let-7a/b/f-5p) and Bim (hsa-miR-24-3p, hsa-miR-25-3p, hsa-miR-221-3p), estrogen synthesis through Cyp19a1 (hsa-let-7a/b/f-5p), POI rescue by targeting Pten (hsa-miR-29a/b-3p, hsa-miR-152-3p) and Pdcd4 (hsa-miR-16-5p, hsa-miR-21-5p, miR-503-5p), and ovarian clock regulation by modulating E4bp4 (hsa-miR-199a/b-5p, hsa-miR-128-3p) and Rev-erb (hsa-miR-24-3p, hsa-miR-432-5p, hsa-miR-185-5p).
In summary, this study is the first to demonstrate the beneficial effects of the ER+pcMSC secretome in restoring ovarian function and circadian rhythm in a mouse model of CTX-induced POI. These results provide new insights into potential stem cell therapies for patients affected by chemotherapy-induced POI.