Induction of Estrogen-Sensitive Epithelial Cells Derived from Human-Induced Pluripotent Stem Cells to Repair Ovarian Function in a Chemotherapy-Induced Mouse Model of Premature Ovarian Failure
Induction of Estrogen-Sensitive Epithelial Cells Derived from Human-Induced Pluripotent Stem Cells to Repair Ovarian Function in a Chemotherapy-Induced Mouse Model of Premature Ovarian Failure
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DOI：
10.1089/dna.2013.2032
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发表时间：
2013-12-01
影响因子：
3.1
通讯作者：
Wang, Jiejun
中科院分区：
文献类型：
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作者：
Liu, Te;Qin, Wenxing;Wang, Jiejun
卵巢早衰(POF)的发病率近年来一直在上升，POF是一种在40岁之前导致闭经和高促性腺激素低雌激素症的疾病。作为一种不可逆转的病理变化，迫切需要改进这种疾病的治疗策略。本研究使用一种microRNA(miR-17-3p)在体外诱导人多能干细胞(IPS)分化为激素敏感的卵巢上皮(OSE)样细胞。为了防止其形态转化为成纤维细胞样细胞，将抑制波形蛋白表达的微RNA MIR-17-3P导入人iPS细胞。随后，经雌激素和细胞生长因子处理后，这些细胞在体外成功地诱导成OSE样细胞。与对照组相比，转染miR-17-3p的iPS细胞表达高水平的上皮标志物(细胞角蛋白7、AE1、AE3和E-钙粘素)和雌激素受体(ER和ER)，而间质标志物(纤维连接蛋白、波形蛋白和N-钙粘附素)表达降低。然后将人iPS细胞来源的OSE样细胞注射到环磷酰胺诱导的POF模型小鼠中，以确定它们作为修复卵巢组织的移植物的潜在益处。在体内，OSE样细胞在POF小鼠卵巢内存活至少14天。与阴性对照组相比，OSE样细胞移植组卵巢组织中细胞角蛋白7和ER蛋白表达上调，纤维连接蛋白和波形蛋白表达下调。此外，与对照组相比，OSE样细胞移植组的卵巢重量和血浆E-2水平随着时间的推移而增加。因此，我们可以得出结论，iPS细胞在体外可以被诱导分化为OSE样细胞。
The incidence of premature ovarian failure (POF), a condition causing amenorrhea and hypergonadotropic hypoestrogenism in women before the age of 40, has been increasing in recent years. As an irreversible pathological change, improved treatment strategies for this disease are urgently needed. In this study, a type of microRNA (miR-17-3p) was used to guide the differentiation of human-induced pluripotent stem (iPS) cells into hormone-sensitive ovarian epithelial (OSE)-like cells in vitro. To prevent their morphological transformation into fibroblast-like cells, MiR-17-3p, a microRNA that suppresses vimentin expression, was transfected into human iPS cells. Subsequently, these cells were successfully induced into OSE-like cells in vitro after treatment with estrogen and cell growth factors. Compared with controls, iPS cells transfected with miR-17-3p expressed higher levels of epithelial markers (cytokeratin 7, AE1, AE3, and E-cadherin) and estrogen receptors (ER and ER) while levels of mesenchymal markers (fibronectin, vimentin, and N-cadherin) lowered after the induction. The human iPS cell-derived OSE-like cells were then injected into cyclophosphamide-induced POF model mice to determine their potential benefit as grafts to repair ovarian tissues. The OSE-like cells survived within POF mouse ovaries for at least 14 days in vivo. Compared with the negative controls, expressions of cytokeratin 7 and ER proteins were elevated while fibronectin and vimentin levels in ovarian tissues were downregulated in the OSE-like cell transplantation group. Moreover, the ovarian weight and plasma E-2 level increased over time in the transplantation with OSE-like cells, compared with control groups. Hence, we can draw the conclusion that iPS cells can be induced to differentiate into OSE-like cells in vitro.