Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway
Ruican Cao, 山东大学生殖医学研究中心(山东大学附属生殖医院), 山东 济南 250012, 中国, Yue Lv, Gang Lü, Hongbin Liu, Wuming Wang, Chunlai Tan, Xianwei Su, Zhiqiang Xiong, Jinlong Ma, Wai‐Yee Chan, 中国科学院动物进化与遗传前沿交叉卓越创新中心香港分中心, 香港, 中国, 香港中文大学-山东大学生殖遗传联合实验室, 香港, 中国, 生殖内分泌教育部重点实验室(山东大学), 山东 济南 250012, 中国, 山东生殖医学重点实验室(山东省第一医科大学附属省立医院), 山东 济南 250012, 中国, 山大生殖香港研发中心, 香港, 中国, 中国科学院昆明动物研究所-香港中文大学（KIZ-CUHK）生物资源与疾病分子机理联合实验室，香港，中国
Abstract
Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma, causing endocrine disorder, reproductive dysfunction, and primary ovarian insufficiency (POI). Recent studies have suggested that extracellular vesicles (EVs) secreted from mesenchymal stem cells (MSCs) exert therapeutic effects in various degenerative diseases. In this study, transplantation of EVs from human induced pluripotent stem cell-derived MSCs (iPSC-MSC-EVs) resulted in significant restoration of ovarian follicle numbers, improved granulosa cell proliferation, and inhibition of apoptosis in chemotherapy-damaged granulosa cells, cultured ovaries, and <i>in vivo</i> ovaries in mice. Mechanistically, treatment with iPSC-MSC-EVs resulted in up-regulation of the integrin-linked kinase (ILK) -PI3K/AKT pathway, which is suppressed during chemotherapy, most likely through the transfer of regulatory microRNAs (miRNAs) targeting ILK pathway genes. This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.