Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis
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Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
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Our single-nuclear RNA-seq in murine MASH models and MASH patients showed enrichment of myofibroblast pathways regulating ECM production and cell migration, including MMPs, TIMPs, and LOXLs.
“We recently used single nuclear RNA-seq in murine MASH models and patients with MASH to demonstrate enrichment of pathways in myofibroblasts that regulate extracellular matrix production and cell migration, including matrix metalloproteinase (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and lysyl oxidases (LOXLs) (47-49), similar to earlier studies of mouse fibrosis and human cirrhosis”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
In experimental MASH and human disease, a subset of hepatocytes expressing the Ephrin B2 receptor can induce cell-autonomous inflammation that provokes fibrosis, making these cells a potential therapeutic target.
“For example, in experimental MASH and human disease a subset of hepatocytes that express the Ephrin B2 receptor can induce cell-autonomous inflammation that provokes fibrosis, establishing these cells as a potential therapeutic target (49).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
Detection of both quiescent and activated HSCs in mouse liver injury models by single-cell RNA-seq supports HSC activation as a driver of fibrosis across etiologies, including MASH.
“The detection of both quiescent and activated HSCs in mouse liver injury models using single cell RNA-seq reinforces HSC activation as a driver of fibrosis common across etiologies that includes MASH (46-50).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
Although activated HSCs are the primary fibrogenic cells in MASH, single-cell methods have identified an expanded list of fibrogenic drivers expressed by activated HSCs that could be antifibrotic drug targets.
“Although activated HSCs are the primary fibrogenic cells in MASH, these methods have identified an expanded list of fibrogenic drivers expressed by activated HSCs that could represent antifibrotic drug targets (42, 48, 49, 125).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
Applying informatic tools and databases uncovered an altered cell-cell communication network in MASH based on differential ligand and receptor expression across cell types.
“Applying recent developments in informatic tools and databases (130, 131) has uncovered an altered cell-cell communication network in MASH based on the differential expression of ligands and receptors in different cell types (48, 49).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
Differential ligand-receptor signaling pairs suggest that disease drivers and signaling events may change as disease advances, so advanced fibrotic stages may respond to different pharmacotherapies than earlier stages.
“These different communication networks are reflected in the differential expression of ligand-receptor signaling pairs, suggesting that the repertoire of disease drivers – and therefore the underlying signaling events – may change as the disease advances, such that advanced fibrotic stages may respond to different pharmacotherapies than earlier stages (48, 49).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
Single-nucleus ATAC-seq of hepatocytes from MASH mice revealed increased NOTCH binding at the EPHB2 locus, upregulating EPHB2 as a driver of MASH fibrosis.
“Recent studies using single nucleus ATAC-seq to profile the epigenome of hepatocytes from MASH mice have revealed increased NOTCH binding in the Ephrin Type-B Receptor 2 (EPHB2) locus, resulting in the upregulation of EPHB2 as a driver of MASH fibrosis (49).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [49]
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- Authors
- Xiao, Y., Batmanov, K., Hu, W., Zhu, K., Tom, A. Y., Guan, D., Jiang, C., Cheng, L., McCright, S. J., Yang, E. C., Lanza, M. R., Liu, Y., Hill, D. A., & Lazar, M. A.
- Affiliations
- University of Pennsylvania (US)
- Guangzhou Laboratory (CN)
- Baylor College of Medicine (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Lazar, Mitchell A.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2023-02-08
- Volume
- 15
- Issue
- 682
- Pages
- eadc9653-eadc9653
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC10234568
- OpenAlex
- W4319459347
- Cited by
- 69
- References
- 58
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 20 · 2023: 9
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Pfizer
- University of Pennsylvania
- National Institutes of Health (DK 19525)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK125602, K08DK116668, P30DK019525, R01DK125573, P30DK050306)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, liver fibrosis, EphB2, hepatocytes, Notch signaling, cell adhesion, cell migration, single-nucleus transcriptomics, epigenomics, NASH progression, therapeutic target
- MeSH terms
- Animals, Humans, Inflammation, Liver, Liver Cirrhosis, Mice, Inbred C57BL, Hepatocytes, Mice, Non-alcoholic Fatty Liver Disease
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