Heat shock pretreatment of mesenchymal stem cells for inhibiting the apoptosis of ovarian granulosa cells enhanced the repair effect on chemotherapy-induced premature ovarian failure.
Heat shock pretreatment of mesenchymal stem cells for inhibiting the apoptosis of ovarian granulosa cells enhanced the repair effect on chemotherapy-induced premature ovarian failure.
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DOI：
10.1186/s13287-018-0964-4
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发表时间：
2018-09-26
影响因子：
7.5
通讯作者：
Fu X
中科院分区：
文献类型：
--
作者：
Chen X;Wang Q;Li X;Wang Q;Xie J;Fu X
卵巢早衰（POF）是育龄期女性化疗的严重并发症。先前的研究表明，骨髓间充质干细胞（MSCs）可以部分修复化疗后受损的卵巢结构和功能。热休克（HS）是一种提高细胞存活率的预处理。本研究旨在探讨人骨髓间充质干细胞对化疗诱导的卵巢早衰的修复作用及其可能的作用机制。分离培养大鼠骨髓间充质干细胞，并进行鉴定。在不同强度HS预处理30 min、1 h、2 h和3 h后，分别于24 h、48 h和72 h检测MSCs凋亡情况，确定最佳处理条件。在优化的HS条件下检测MSCs的凋亡和细胞增殖变化。HS预处理的MSCs加入磷芥（PM）模拟化疗微环境后，检测细胞凋亡。分离培养大鼠颗粒细胞。加入PM，与预处理的MSCs共培养后检测GCs的凋亡。建立化疗性卵巢早衰大鼠模型，将经预处理的骨髓间充质干细胞注入双侧卵巢。通过卵巢重量、卵泡数、动情周期和性激素水平评价卵巢结构和内分泌功能。TUNEL法检测胃癌细胞凋亡。HS预处理1h的MSCs凋亡率明显降低，以1h为最佳处理时间。在此条件下，凋亡率的降低持续到预处理后120 h，细胞增殖加速。HS预处理后，MSCs对化疗微环境的耐受性增强。与HS预处理的MSCs共培养后，PM诱导的GC凋亡减少。将预处理的MSC注射到大鼠卵巢中引起卵巢重量和在雌二醇水平的不同阶段的卵泡数量增加，并且在POF模型中引起卵泡刺激素水平和GCs凋亡的降低。HS预处理可增强MSCs对化疗诱导的POF的修复作用。其原因可能是MSC的活力进一步增强，从而导致更大程度地抑制GCs的凋亡。
Premature ovarian failure (POF) is a severe complication associated with chemotherapy for female patients of childbearing age. A previous study has shown that bone marrow-derived mesenchymal stem cells (MSCs) can partially repair the damaged ovarian structure and function following chemotherapy. Heat shock (HS) is a pretreatment to enhance cell survival. The present study aimed to demonstrate the repair effect and potential working mechanism of HS MSCs on chemotherapy-induced POF. Rat MSCs were isolated, cultured and identified. At 24 h, 48 h and 72 h after different strengths of HS pretreatment for 30 min, 1 h, 2 h and 3 h, apoptosis of MSCs was detected to determine the optimal conditions. Apoptosis and cell proliferation changes of MSCs were detected under the optimal conditions of HS. Apoptosis of HS preconditioned MSCs was detected after adding phosphamide mustard (PM) to mimic the microenvironment under chemotherapy. Rat granulosa cells (GCs) were isolated and cultured. PM was added and apoptosis of GCs was detected after coculture with the pretreated MSCs. The rat model of chemotherapy-induced POF was established and the pretreated MSCs were injected into bilateral ovaries. Ovarian structure and endocrine function were evaluated by ovary weight, follicle count, estrous cycle and sex hormone levels. Apoptosis of GCs was detected by TUNEL assay. The apoptosis rate of MSCs with 1 h of HS pretreatment decreased significantly, so 1 h was considered the optimal duration. Under this condition, the reduction in the apoptosis rate persisted until 120 h after the pretreatment and cell proliferation was accelerated. After HS pretreatment, MSCs displayed an increased tolerance to microenvironment under chemotherapy. After coculture with the HS-pretreated MSCs, PM-induced apoptosis of GCs decreased. Injection of the pretreated MSCs into the rat ovaries caused an increase in ovary weight and the number of follicles at different stages of estradiol levels, and a decrease in follicle stimulating hormone levels and apoptosis of GCs in the POF model. HS pretreatment enhanced the repair effect of MSCs on chemotherapy-induced POF. The reason for this may be the further vitality enhancement of MSCs, which led to a greater inhibition of apoptosis of GCs.
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