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 in vivo 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.
化疗是导致育龄期妇女生育力下降的重要原因，可使卵巢组织中的卵泡数量严重下降，从而引起内分泌紊乱、生殖功能障碍或原发性卵巢功能不全（POI）。最近的研究表明，间充质干细胞分泌的细胞外囊泡在许多退行性疾病中都可以发挥治疗作用。该研究发现，移植来自人类诱导多能干细胞衍生的间充质干细胞（iPSC-MSCs）的细胞外囊泡（EVs），可明显减轻化疗引起的POI小鼠模型的卵巢损伤，恢复卵巢卵泡数量，改善颗粒细胞增殖，并抑制化疗引起的小鼠颗粒细胞、体外培养的卵巢和POI小鼠卵巢中的凋亡。进一步的研究发现，iPSC-MSC-EVs的处理可以激活ILK-PI3K/AKT通路的上调，逆转了化疗引起的ILK-PI3K/AKT通路的下调，进而抑制了细胞的凋亡，加速细胞周期和促进细胞增殖。iPSC-MSC-EVs富含miRNAs，体外实验的结果表明，iPSC-MSC-EVs可能是通过转移靶向ILK通路基因的功能性miRNAs发挥作用。总的来说，该研究为改善女性化疗患者的卵巢损伤和提高POI患者的卵巢功能的治疗方法提供了一个新思路，并初步阐明了iPSC-MSC-EVs减轻化疗引起的卵巢损伤的基本分子机制。.
Keywords: Extracellular vesicles; Human induced pluripotent stem cell-derived mesenchymal stem cells; ILK-PI3K/AKT pathway; Premature ovarian insufficiency.