Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease

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 fundame...

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Published in:Science translational medicine 2024-04, Vol.16 (744), p.eadk6213-eadk6213
Main Authors: Hu, Po, Rychik, Jack, Zhao, Juanjuan, Bai, Huajun, Bauer, Aidan, Yu, Wenbao, Rand, Elizabeth B, Dodds, Kathryn M, Goldberg, David J, Tan, Kai, Wilkins, Benjamin J, Pei, Liming
Format: Article
Language:English
Subjects:
Activin
Cell activation
Epigenomics
Fibrosis
Fontan Procedure - adverse effects
Heart diseases
Hepatic Stellate Cells - metabolism
Hepatic Stellate Cells - pathology
Hepatocytes
Hepatocytes - metabolism
Humans
Liver - metabolism
Liver - pathology
Liver cirrhosis
Liver Cirrhosis - etiology
Liver Cirrhosis - pathology
Liver diseases
Liver Diseases - ethnology
Liver Diseases - pathology
Multiomics
Pathogenesis
Single-Cell Analysis
snRNA
Stellate cells
Therapeutic targets
Transcription activation
Transcriptome
Transcriptomics
Ventricle
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Summary: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.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.adk6213