Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan.
Int J Mol Sci. 2024 Jul 20;25(14):7948. doi: 10.3390/ijms25147948.
Polycystic ovary syndrome (PCOS) is a female endocrine disorder with metabolic issues. Hyperandrogenism combined with hyperinsulinemia exacerbates the reproductive, metabolic, and inflammatory problems in PCOS patients. The etiology of PCOS is unclear. Patient-specific induced pluripotent stem cells (iPSCs) offer a promising model for studying disease mechanisms and conducting drug screening. Here, we aim to use mesenchymal progenitor cells (MPCs) derived from PCOS iPSCs to explore the mechanism of PCOS. We compared the transcriptome profiles of PCOS and healthy control (HC) iPSC-derived MPCs (iPSCMs). Moreover, we assess the impact of androgens on iPSCMs. In the comparison between PCOS and HC, the expression levels of 1026 genes were significantly different. A gene set enrichment analysis (GSEA) revealed that adipogenesis- and metabolism-related genes were downregulated, whereas inflammation-related genes were upregulated in the PCOS iPSCMs. Dysregulation of the TGF-β1 and Wnt signaling pathways was observed in the PCOS iPSCMs. Furthermore, there was impaired adipogenesis and decreased lipolysis in the PCOS iPSCMs-derived adipocytes. With testosterone treatment, genes related to metabolism were upregulated in the HC iPSCMs but downregulated in the PCOS iPSCMs. The impact of testosterone varied among HCs and PCOS iPSCMs, possibly because of a genetic predisposition toward PCOS. This study found specific signaling pathways that could serve as therapeutic targets for PCOS.
多囊卵巢综合征（PCOS）是一种女性内分泌疾病，伴有代谢问题。高雄激素血症合并高胰岛素血症可加重 PCOS 患者的生殖、代谢和炎症问题。PCOS 的病因尚不清楚。患者特异性诱导多能干细胞（iPSCs）为研究疾病机制和进行药物筛选提供了有前途的模型。在这里，我们旨在使用源自 PCOS iPSCs 的间充质祖细胞（MPCs）来探索 PCOS 的发病机制。我们比较了 PCOS 和健康对照（HC）iPSC 衍生的 MPC（iPSCM）的转录组谱。此外，我们评估了雄激素对 iPSCM 的影响。在 PCOS 与 HC 的比较中，有 1026 个基因的表达水平有显著差异。基因集富集分析（GSEA）显示，PCOS iPSCM 中脂肪生成和代谢相关基因下调，而炎症相关基因上调。在 PCOS iPSCM 中观察到 TGF-β1 和 Wnt 信号通路的失调。此外，PCOS iPSCM 来源的脂肪细胞中脂肪生成受损，脂肪分解减少。用睾酮处理后，HC iPSCM 中与代谢相关的基因上调，但 PCOS iPSCM 中下调。睾酮的影响在 HC 和 PCOS iPSCM 之间存在差异，这可能是由于 PCOS 的遗传易感性。本研究发现了一些特定的信号通路，它们可能成为 PCOS 的治疗靶点。
