Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis
Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis
复制标题
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
DOI：
10.1126/scitranslmed.abd1206
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发表时间：
2021
影响因子：
17.1
通讯作者：
Zho
中科院分区：
文献类型：
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作者：
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.Friedman;Liping Chen;Bi-Sen Ding;Zho
描述表观遗传靶向纤维化肝脏中适应不良的血管生态位，通过减轻纤维化血管分泌IGFBP 7和ADAMTS 1阻断纤维化。导致非酒精性脂肪性肝炎（NASH）纤维形成的分子过程是复杂的，尚未完全了解。Zhang等人使用多个物种的单细胞组学分析表明，肝内皮细胞的表观遗传失调促进了这些细胞从窦状隙到血管表型的适应不良。血管适应不良的细胞通过HDAC 2-DNMT 1-IGFBP 7-TH 17途径刺激纤维化，靶向该途径的HDAC 2和DNMT 1抑制剂减轻了小型猪NASH模型中的纤维化。这为研究NASH的发病机制提供了宝贵的资源，并提出了一种潜在的策略，以阻止这种疾病中血管适应不良所促进的肝纤维化。慢性肝病如非酒精性脂肪性肝炎（NASH）抑制肝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，NASH是一种日益增长的健康挑战，没有批准的治疗方法。在这里，我们使用多组学分析人类肝硬化，西方饮食和四氯化碳（CCl 4）诱导的小型猪NASH模型，以及基因修饰小鼠，以揭示单细胞水平的血管适应组的景观，其中内皮细胞（EC）和TH 17细胞共同导致肝硬化。我们发现，表观遗传学依赖的肝血管适应不良富集了纤维化TH 17细胞，从而促进了小鼠、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（HDAC 2）和DNA甲基转移酶1（DNMT 1）之间的串扰促进肝脏EC适应不良，以促进细胞外囊泡中血管分泌IGFBP 7和ADAMTS 1的产生，从而将纤维化TH 17细胞招募到肝脏。HDAC 2和DNMT 1的药理学靶向减轻了小型猪NASH模型中的纤维化。我们的结论是，表观遗传重编程血管适应有助于肝纤维化。靶向血管适应性淋巴结可能会阻止适应不良的血管形成，以促进NASH的肝脏再生。
Description Epigenetic targeting of the maladaptive vascular niche in fibrotic liver blocks fibrosis by alleviating fibrogenic angiocrine IGFBP7 and ADAMTS1. Epigenetic bad actors in liver fibrosis The molecular processes that lead to fibrogenesis in nonalcoholic steatohepatitis (NASH) are complex and not completely understood. Zhang et al. used single-cell omics analysis of multiple species to show that epigenetic dysregulation of hepatic endothelial cells promoted the maladaptation of these cells from a sinusoidal to vascular phenotype. The vascularly maladapted cells stimulated fibrosis via a HDAC2-DNMT1-IGFBP7-TH17 pathway, and HDAC2 and DNMT1 inhibitors targeting this pathway mitigated fibrosis in a minipig NASH model. This provides a valuable resource for studying NASH pathogenesis and suggests a potential strategy to block the liver fibrosis promoted by maladaptive vascularization in this disease. 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.