Department of Reproductive Genetics, Heping Hospital of Changzhi Medical College, Changzhi, 046000, P.R. China.
Institute of Reproduction and Genetics of Changzhi Medical College, Changzhi, 046000, P.R. China.
J Ovarian Res. 2024 Nov 14;17(1):224. doi: 10.1186/s13048-024-01536-8.
Premature ovarian insufficiency (POI) is a disease with medical, psychological and reproductive implications, but its common therapies have limited efficacy and a likelihood of complications. This study delves into the therapeutic role of human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSCs-EVs) in POI mice through the insulin-like growth factor 1 (IGF-1)/nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/autophagy pathway.
hUC-MSCs were transfected with lentiviral short hairpin RNA of IGF-1 before EV extraction. Cyclophosphamide (CTX)-induced POI mouse models were administrated with hUC-MSCs-EVs. Mouse ovarian granulosa cells (GCs) were induced with CTX, then treated with hUC-MSCs-EVs and ML385. Ovarian histopathological changes were observed, changes in follicle number at all levels were counted and serum sex hormones were evaluated, as well as LC3II/I and Beclin-1 expression. GCs were subject to detection of proliferation, deaths, oxidative stress, and Nrf2 nuclear translocation.
After CTX exposure, mice showed thinner GCs layer in the ovary, reduced number of GCs and follicles at all levels, disturbed serum sex hormones, enhanced oxidative stress and autophagy, and downregulated ovarian IGF-1; whereas, hUC-MSCs-EVs upregulated IGF-1 to improve the ovarian function. hUC-MSCs-EVs carrying IGF-1 activated Nrf2/HO-1 signaling to inhibit CTX-induced excessive autophagy of GCs, but this ameliorative effect was partially weakened by inhibiting Nrf2/HO-1 signaling. hUC-MSCs-EVs inhibited excessive autophagy of GCs and improved ovarian function of CTX-induced mice through IGF-1/Nrf2/HO-1 pathway.
hUC-MSCs-EVs activate the Nrf2/HO-1 signaling by carrying IGF-1, which in turn inhibits excessive autophagy and damage of GCs, thus improving ovarian function in POI mice.
卵巢早衰（POI）是一种具有医学、心理和生殖影响的疾病，但常用的治疗方法疗效有限且可能存在并发症。本研究通过胰岛素样生长因子 1（IGF-1）/核因子 E2 相关因子 2（Nrf2）/血红素加氧酶-1（HO-1）/自噬途径探讨人脐带间充质干细胞衍生的细胞外囊泡（hUC-MSCs-EVs）在 POI 小鼠中的治疗作用。
提取 hUC-MSCs 的 EV 前，用慢病毒短发夹 RNA 转染 IGF-1。用环磷酰胺（CTX）诱导 POI 小鼠模型，给予 hUC-MSCs-EVs。用 CTX 诱导小鼠卵巢颗粒细胞（GCs），然后用 hUC-MSCs-EVs 和 ML385 处理。观察卵巢组织病理学变化，计数各级卵泡数，评估血清性激素水平，检测 LC3II/I 和 Beclin-1 的表达。检测 GCs 的增殖、死亡、氧化应激和 Nrf2 核转位。
CTX 暴露后，小鼠卵巢 GC 层变薄，各级 GC 和卵泡数减少，血清性激素紊乱，氧化应激和自噬增强，卵巢 IGF-1 下调；而 hUC-MSCs-EVs 上调 IGF-1 改善卵巢功能。hUC-MSCs-EVs 携带 IGF-1 激活 Nrf2/HO-1 信号通路，抑制 CTX 诱导的 GCs 过度自噬，但抑制 Nrf2/HO-1 信号通路可部分减弱这种改善作用。hUC-MSCs-EVs 通过 IGF-1/Nrf2/HO-1 通路抑制 GCs 过度自噬，改善 CTX 诱导的 POI 小鼠的卵巢功能。
hUC-MSCs-EVs 通过携带 IGF-1 激活 Nrf2/HO-1 信号通路，进而抑制 GCs 的过度自噬和损伤，从而改善 POI 小鼠的卵巢功能。
