Multi‐omics profiling of primary hepatic stellate cells from advanced liver fibrosis patients reveals distinctive molecular signatures

肝星状细胞 转录组 肝硬化 纤维化 小桶 下调和上调 肝纤维化 基因表达谱 医学 生物 癌症研究 病理 基因 基因表达 内科学 遗传学
作者
Yutong Dong,Yuwei Liu,Xu Liu,Heming Ma,Yahui Liu,Guoyue Lv,Junqi Niu
出处
期刊:Journal of Gastroenterology and Hepatology [Wiley]
卷期号:38 (8): 1416-1425 被引量:3
标识
DOI:10.1111/jgh.16221
摘要

Abstract Background and Aim Hepatic fibrosis is a common pathogenic outcome of almost all chronic liver diseases and a growing public health problem globally. However, the key genes or proteins driving liver fibrosis and cirrhosis are not well understood. We aimed to identify novel hepatic fibrosis genes of human primary hepatic stellate cells (HSCs). Methods Human primary HSCs were isolated from surgically resected advanced fibrosis liver tissues ( n = 6) and surgical resection of normal liver tissue around hemangioma ( n = 5). Differences in the expression levels of mRNA and proteins from HSCs in advanced fibrosis group and the control group were analyzed using RNA sequencing and mass spectrometry as transcriptomic and proteomic approaches. The obtained biomarkers were further validated through real‐time quantitative polymerase chain reaction (RT‐qPCR), immunofluorescence, and Western blot. Results A total of 2156 transcripts and 711 proteins were found to be differently expressed between the advanced fibrosis group and the control group patients. The Venn diagram shows that a total of 96 upregulated molecules are overlapped in both the transcriptomic and proteomic datasets. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis indicated that those overlapped genes were mainly involved in wound healing, cell adhesion regulation, and actin binding, which reflects the major biological conversions in liver cirrhosis process. Pyruvate kinase M2 and EH domain‐containing 2 were identified as potential new markers for advanced liver cirrhosis, which have been validated in primary human HSCs and in vitro cellular hepatic fibrosis model Lieming Xu‐2 (LX‐2) cells. Conclusions Our results revealed the major transcriptomic and proteomic changes during liver cirrhosis process and identified new biomarkers and potential therapeutic targets for advanced liver fibrosis.
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