Myeloid TGF-b signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis
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ABSTRACT:
PROVIDER: PRJNA1142583 | ENA |
REPOSITORIES: ENA
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Project description:Cellular heterogeneity of innate immune cells such as macrophages is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis. The mechanisms shaping liver macrophage heterogeneity and polarization during disease progression remain poorly understood. Here we identified TGF-b signaling as a critical regulator of the bifurcate maturation of TREM2+ and NEGR1+ macrophages in MASH liver. Myeloid-specific inactivation of Tgfbr1 in mice exacerbated diet-induced MASH pathologies, including hepatocyte injury, inflammation, and liver fibrosis. Mechanistically, ablation of TGF-b signaling in myeloid cells resulted in diminished TREM2+ macrophages and a marked expansion of NEGR1+ macrophages in the liver. The latter is characterized by induction of gene signatures associated with inflammasome activation, cytokine signaling, cellular senescence, and immunosuppression. The expansion of NEGR1+ macrophage contributes to effector T cell exhaustion, thereby facilitating the development of MASH-associated hepatocellular carcinoma in Tgfbr1-deficient mice. Together, these studies uncover myeloid TGF-b signaling as a crucial factor within the liver microenvironment that shapes liver macrophage heterogeneity and functional polarization during MASH pathogenesis and the development of MASH-associated liver cancer.
2025-09-01 | GSE273661 | GEO
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Project description:Disruption of the epigenome is a hallmark of human disease including liver cirrhosis and hepatocellular carcinoma (HCC). While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures including hepatitis C viral (HCV) infection and metabolic syndrome alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target the most frequently mutated genes in HCC, there is an unmet need for novel therapeutic strategies to prevent or reverse hepatic tumorigenesis, which the epigenome may provide. We performed genome-wide profiling of DNA methylation, copy number, and gene expression landscapes from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contribution of these processes to liver disease progression. We identify epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity associates with increases in gene expression heterogeneity. Cirrhotic regions comprise two distinct cohorts, one exclusively epigenetic, and a second where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (e.g., HNF1A) and known tumor suppressors (e.g., RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in cell line functional screens, supporting their relevance to hepatocarcinogenesis. Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.
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