肝硬化
癌症研究
适应不良
纤维化
脂肪性肝炎
肝星状细胞
内科学
医学
病理
生物
表观遗传学
脂肪肝
免疫学
疾病
遗传学
基因
作者
Hua Zhang,Yongyuan Ma,Xiaoli Cheng,Dongbo Wu,Xingming Huang,Bin Chen,Yafeng Ren,Wei Jiang,Xiaoqiang Tang,Ting Bai,Yutian Chen,Yilin Zhao,Chunxue Zhang,Xia Xiao,Jing Liu,Yelin Deng,Tinghong Ye,Lu Chen,Hanmin Liu,Scott L. Friedman,Liping Chen,Bi‐Sen Ding,Zhongwei Cao
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-10-06
卷期号:13 (614)
被引量:22
标识
DOI:10.1126/scitranslmed.abd1206
摘要
Chronic hepatic diseases such as nonalcoholic steatohepatitis (NASH) suppress liver regeneration and lead to fibrosis and cirrhosis. Decoding the cellular and molecular network underlying this fibrotic maladaptation might aid in combatting NASH, a growing health challenge with no approved therapies. Here, we used multiomics analysis of human cirrhotic liver, a Western diet– and carbon tetrachloride (CCl4)–induced minipig NASH model, and genetically modified mice to unravel the landscape of the vascular adaptome at the single-cell level, in which endothelial cells (ECs) and TH17 cells jointly contribute to liver cirrhosis. We found that epigenetics-dependent hepatic vascular maladaptation enriches fibrogenic TH17 cells to promote liver fibrosis in mice, minipigs, and human patients with cirrhosis. Further analysis of humans, minipigs, and mice suggested that cross-talk between histone deacetylase 2 (HDAC2) and DNA methyltransferase 1 (DNMT1) promoted liver EC maladaptation to promote production of angiocrine IGFBP7 and ADAMTS1 in extracellular vesicles, recruiting fibrogenic TH17 cells to the liver. Pharmacological targeting of HDAC2 and DNMT1 alleviated fibrosis in a minipig NASH model. We conclude that epigenetically reprogrammed vascular adaptation contributes to liver fibrosis. Targeting of a vascular adaptation node might block maladaptive vascularization to promote liver regeneration in NASH.
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