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 T_H17 cells jointly contribute to liver cirrhosis. We found that epigenetics-dependent hepatic vascular maladaptation enriches fibrogenic T_H17 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 T_H17 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.

中文翻译：

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靶向表观遗传适应不良的血管生态位可减轻非酒精性脂肪性肝炎的肝纤维化

慢性肝病如非酒精性脂肪性肝炎 (NASH) 会抑制肝脏再生并导致纤维化和肝硬化。解码这种纤维化适应不良背后的细胞和分子网络可能有助于对抗 NASH，这是一种日益严重的健康挑战，没有经过批准的疗法。在这里，我们对人类肝硬化肝脏、西方饮食和四氯化碳 (CCl ₄ ) 诱导的小型猪 NASH 模型和转基因小鼠进行了多组学分析，以揭示单细胞水平的血管适应组的情况，其中内皮细胞 (EC) 和 T _H 17 细胞共同导致肝硬化。我们发现表观遗传学依赖性肝血管适应不良会丰富纤维化 T _H17 细胞促进小鼠、小型猪和人类肝硬化患者的肝纤维化。对人类、小型猪和小鼠的进一步分析表明，组蛋白去乙酰化酶 2 (HDAC2) 和 DNA 甲基转移酶 1 (DNMT1) 之间的交互作用促进了肝脏 EC 适应不良，从而促进细胞外囊泡中血管分泌 IGFBP7 和 ADAMTS1 的产生，募集纤维化 T _H 17 细胞到肝脏。HDAC2 和 DNMT1 的药理学靶向缓解了小型猪 NASH 模型中的纤维化。我们得出结论，表观遗传重编程的血管适应有助于肝纤维化。靶向血管适应节点可能会阻止适应不良的血管形成，以促进 NASH 中的肝再生。