Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis

Hua Zhang, Yongyuan Ma, Xinying 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, Yue Deng, Tinghong Ye, Lu Chen, Han Min Liu, Scott L. FriedmanLiping Chen, Bi Sen Ding, Zhongwei Cao

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish
Article numbereabd1206
JournalScience Translational Medicine
Issue number614
StatePublished - 6 Oct 2021


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