Logan Philip C, Yango Pamela, Tran Nam D
1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
Reprod Sci. 2018 Jan;25(1):140-159. doi: 10.1177/1933719117704905. Epub 2017 May 11.
Endometriosis is a chronic inflammatory disease that causes pain and infertility in women of reproductive age.
To investigate the pathologic pathways in endometrial stromal and epithelial cells that contribute to the manifestation of endometriosis.
In vitro cellular and molecular analyses of isolated eutopic endometrial stromal and epithelial cells.
Eutopic stromal and epithelial cells from endometriotic and normal patients were isolated by fluorescence-activated cell sorting for paired sibling RNA sequencing and microRNA microarray. Aberrant pathways were identified using ingenuity pathway analysis networks and confirmed with in vitro modulation of the affected pathways in stromal and epithelial cell cultures.
Both stromal versus epithelial cell types and paired endometriotic versus normal samples exhibited distinct hierarchical clustering. Compared to normal samples, there were 151 and 215 differentially expressed genes in the endometriotic stromal and epithelial populations, respectively, and concomitantly 9 and 16 differentially expressed microRNAs. Overall, endometriotic stromal and epithelial cells revealed distinct defects. In endometriotic stromal cells, key decidualization genes Zinc finger E-box Binding protein 1 (ZEB1), Heart And Neural crest Derivatives expressed 2 (HAND2), WNT4, and Interleukin 15 (IL-15) were found to be downregulated and Periostin (POSTN) and Matrix Metallopeptidase 7 (MMP7) were upregulated. Specifically, ZEB1 was downregulated in stromal cells by aberrant elevation in miR-200b. In contrast, ZEB1 was found to be upregulated in endometriotic epithelial cells through associated upregulation of transforming growth factor β1 (TGFβ1), inducer of the TGFβ1-Bone Morphogenetic Protein 2 (BMP2)-MMP2-Prostaglandin-endoperoxide Synthase 2 (COX2)-ZEB1 pathway, which activates epithelial-mesenchymal transition.
Manifestation of endometriosis involves dysregulation of unique molecular pathways within the diseased endometrial stromal and epithelial cells in the endometrium. Targeting the cell type-specific defects may offer a novel approach to treating endometriosis.
子宫内膜异位症是一种慢性炎症性疾病，可导致育龄期女性出现疼痛和不孕。
研究子宫内膜间质细胞和上皮细胞中导致子宫内膜异位症表现的病理途径。
对分离出的在位子宫内膜间质细胞和上皮细胞进行体外细胞和分子分析。
通过荧光激活细胞分选从子宫内膜异位症患者和正常患者中分离出在位间质细胞和上皮细胞，用于配对同胞RNA测序和微小RNA微阵列分析。使用 Ingenuity 通路分析网络鉴定异常途径，并通过体外调节间质细胞和上皮细胞培养物中受影响的途径进行确认。
间质细胞与上皮细胞类型以及配对的子宫内膜异位症样本与正常样本均表现出明显的分层聚类。与正常样本相比，子宫内膜异位症间质细胞和上皮细胞群体中分别有151个和215个差异表达基因，同时有9个和16个差异表达的微小RNA。总体而言，子宫内膜异位症间质细胞和上皮细胞显示出明显的缺陷。在子宫内膜异位症间质细胞中，关键的蜕膜化基因锌指E盒结合蛋白1（ZEB1）、心脏和神经嵴衍生物表达2（HAND2）、WNT4和白细胞介素15（IL-15）被发现下调，骨膜蛋白（POSTN）和基质金属蛋白酶7（MMP7）上调。具体而言，miR-200b异常升高导致间质细胞中ZEB1下调。相反，在子宫内膜异位症上皮细胞中，通过转化生长因子β1（TGFβ1）、TGFβ1-骨形态发生蛋白2（BMP2）-MMP2-前列腺素内过氧化物合酶2（COX2）-ZEB1通路的相关上调发现ZEB1上调，该通路激活上皮-间质转化。
子宫内膜异位症的表现涉及患病子宫内膜间质细胞和上皮细胞内独特分子途径的失调。针对细胞类型特异性缺陷可能为治疗子宫内膜异位症提供一种新方法。
