The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type–specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first “responder” in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A’s transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

中文翻译：

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单细胞多组学指导 Fontan 相关肝病的机制理解

Fontan手术是目前单心室先天性心脏病的标准治疗方法。患有 Fontan 循环 (FC) 的个体表现出中心静脉高压，并面临危及生命的肝纤维化并发症，称为 Fontan 相关肝病 (FALD)。 FALD 的基本生物学和机制尚不清楚。在这里，我们使用多组学 snRNA-ATAC-seq 以单细胞分辨率生成了人类 FALD 的转录组和表观基因组图谱。我们在 FC 肝脏中发现了深刻的细胞类型特异性转录组和表观基因组变化。中央肝细胞（cHep）表现出最实质性的变化，其特点是深刻的代谢重编程。这些 cHep 变化先于肝星状细胞的大量激活和肝纤维化，表明 cHep 是 FALD 发病机制中潜在的第一“反应者”。我们还发现了一个配体-受体对网络，将信号从 cHep 传递到肝星状细胞，这可能促进其活化和肝纤维化。我们进一步通过实验证明激活素 A 和 B 在体外促进纤维化激活，并确定了激活素 A 在 FALD 中转录激活的机制。我们的单细胞转录组和表观基因组图谱共同揭示了 FALD 发病机制的机制见解，并可能有助于识别潜在的治疗靶点。