Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Prentice Women's Hospital, 250 E. Superior Street, Room 3-2306, Chicago, IL 60611, USA; Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Prentice Women's Hospital, 250 E. Superior Street, Room 3-2306, Chicago, IL 60611, USA.
Stem Cell Reports. 2018 Nov 13;11(5):1136-1155. doi: 10.1016/j.stemcr.2018.10.002. Epub 2018 Nov 1.
Defective endometrial stromal fibroblasts (EMSFs) contribute to uterine factor infertility, endometriosis, and endometrial cancer. Induced pluripotent stem cells (iPSCs) derived from skin or bone marrow biopsies provide a patient-specific source that can be differentiated to various cells types. Replacement of abnormal EMSFs is a potential novel therapeutic approach for endometrial disease; however, the methodology or mechanism for differentiating iPSCs to EMSFs is unknown. The uterus differentiates from the intermediate mesoderm (IM) to form coelomic epithelium (CE) followed by the Müllerian duct (MD). Here, we successfully directed the differentiation of human iPSCs (hiPSCs) through IM, CE, and MD to EMSFs under molecularly defined embryoid body culture conditions using specific hormonal treatments. Activation of CTNNB1 was essential for expression of progesterone receptor that mediated the final differentiation step of EMSFs before implantation. These hiPSC-derived tissues illustrate the potential for iPSC-based endometrial regeneration for future cell-based treatments.
缺陷的子宫内膜基质成纤维细胞（EMSFs）是导致子宫因素不孕、子宫内膜异位症和子宫内膜癌的原因之一。诱导多能干细胞（iPSCs）可从皮肤或骨髓活检中获得，为患者提供了一种特定的来源，可分化为各种细胞类型。替换异常的 EMSFs 是子宫内膜疾病的一种潜在的新型治疗方法；然而，将 iPSCs 分化为 EMSFs 的方法或机制尚不清楚。子宫从中胚层（IM）分化形成体腔上皮（CE），然后形成苗勒管（MD）。在这里，我们在分子定义的胚状体培养条件下，使用特定的激素处理，成功地将人诱导多能干细胞（hiPSCs）通过 IM、CE 和 MD 诱导分化为 EMSFs。CTNNB1 的激活对于孕激素受体的表达是必需的，孕激素受体介导了植入前 EMSFs 的最后分化步骤。这些 hiPSC 衍生组织说明了基于 iPSC 的子宫内膜再生用于未来基于细胞的治疗的潜力。
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