单细胞转录揭示了胆道闭锁中肝细胞到胆管细胞的重编程和胆道基因谱。

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2025-05-06 eCollection Date: 2025-05-01 DOI:10.1097/HC9.0000000000000710
Lingdu Meng, Min Du, Haodong Li, Fanyang Kong, Jiajian Yang, Rui Dong, Shan Zheng, Gong Chen, Zhen Shen, Junfeng Wang
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引用次数: 0

摘要

背景:胆管反应(DR)是胆道闭锁(BA)的典型肝脏病理,其特征是胆道上皮细胞在门静脉区扩张。DR的细胞来源和功能仍然知之甚少。在此,我们对BA进行了单细胞RNA测序(scRNA-seq),以解决BA中DR的复杂性。方法:对4例BA肝和3例正常对照肝进行scrna测序。从所有细胞中提取上皮细胞进行进一步分析。测定上皮细胞的细胞类型、功能和分化轨迹。通过结合公共批量和scRNA-seq数据鉴定胆道标志物和转录因子(tf),并通过免疫组织化学验证。结果:ScRNA-seq鉴定BA中存在胆道重编程,重编程细胞同时表达肝细胞和胆管细胞标记物。与肝细胞相比,胆管细胞中上皮-间质转化、纤维化、炎症和RNA代谢基因丰富,BA中上调。伪时间分析描述了BA从肝细胞跨越重编程细胞到胆管细胞的分化轨迹。确定基质金属蛋白酶7 (Matrix metalloproteinase 7, MMP7)、VTCN1和LAMC2为胆道标志物,确定KLF5和HNF1B为胆道tf。与对照组相比,BA组所有胆道标志物和tf均上调。结论:解剖胆管细胞的细胞来源和功能,对了解DR在BA中的病理作用至关重要。所鉴定的特异性胆道标志物和tf为未来BA的潜在诊断和机制探索提供了重要的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia.

Background: Ductular reaction (DR), characterized by the expansion of biliary epithelial cells in the portal area, is a typical hepatic pathology for biliary atresia (BA). The cellular source and function of DR remain poorly understood. Herein, we performed single-cell RNA sequencing (scRNA-seq) in BA to resolve the complexity of DR in BA.

Methods: A total of 4 BA and 3 normal control livers underwent scRNA-seq. The epithelial cells were extracted from all cells for further analysis. The cell types, functions, and differentiational trajectory of epithelial cells were determined. The biliary markers and transcription factors (TFs) were identified by combing public bulk and scRNA-seq data and validated by immunohistochemistry.

Results: ScRNA-seq identified the existence of biliary reprogramming in BA, and the reprogrammed cells expressed both hepatocyte and cholangiocyte markers. When compared with hepatocytes, genes of epithelial-mesenchymal transition, fibrosis, inflammation, and RNA metabolism were enriched in cholangiocytes and upregulated in BA. Pseudotime analysis depicted a differentiation trajectory from hepatocytes across reprogrammed cells to cholangiocytes in BA. Matrix metalloproteinase 7 (MMP7), VTCN1, and LAMC2 were identified as the biliary markers, and KLF5 and HNF1B were determined as the biliary TFs in BA. All the biliary markers and TFs were upregulated in BA when compared with controls.

Conclusions: Dissecting the cellular source and function of cholangiocytes is essential to understand the pathological role of DR in BA. The identified specific biliary markers and TFs provide important insights into its potential diagnosis and mechanism exploration for BA in the future.

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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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