ArticleHepatology (Baltimore, Md.)2021
Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 46 citations in OpenAlex.
- SOX9 promotes hepatocyte proliferation via upregulating TGF-α expression during liver regeneration.Hepatology international · 2026Article
- EGF Receptor Activation Stimulates SOX9 Expression in Injured Renal Proximal Tubule Epithelial Cells.Journal of the American Society of Nephrology : JASN · 2026Article
- Massive hepatic necrosis-associated acute liver failure.eGastroenterology · 2026Review
- Exosomes From Intestinal Epithelial Cells Promote Hepatic Differentiation of Liver Progenitor Cells in Gut-Liver-on-a-Chip Models.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish.Nature communications · 2025Article
- Iron-Quercetin complex enhances mesenchymal stem cell-mediated HGF secretion and c-Met activation to ameliorate acute kidney injury through the prevention of tubular cell apoptosis.Regenerative therapy · 2025Article
- Mechanisms and aetiology-dependent treatment of acute liver failure.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Sex disparities in hepatocellular carcinoma immunotherapy: hormonal and genetic influences on treatment efficacy.Frontiers in immunology · 2025Review
- SOX9: a key transcriptional regulator in organ fibrosis.Frontiers in pharmacology · 2025Review
- Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity.bioRxiv : the preprint server for biology · 2024Article
- Application of mesenchymal stem cells in liver fibrosis and regeneration.Liver research (Beijing, China) · 2024Review
- Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases.Genes & diseases · 2024Review
- SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway.Investigative ophthalmology & visual science · 2024Article
- Using different zebrafish models to explore liver regeneration.Frontiers in cell and developmental biology · 2024Review
- PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.Scientific reports · 2023Article
- Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases.Cell insight · 2023Review
- Review
- Article
- Bipotent transitional liver progenitor cells contribute to liver regeneration.Nature genetics · 2023Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimsThe liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver injury settings. In chronic liver diseases, the number of liver progenitor cells (LPCs) correlates proportionally to disease severity, implying that their inefficient differentiation into hepatocytes exacerbates the disease. Moreover, LPCs secrete proinflammatory cytokines; thus, their prolonged presence worsens inflammation and induces fibrosis. Promoting LPC-to-hepatocyte differentiation in patients with advanced liver disease, for whom liver transplantation is currently the only therapeutic option, may be a feasible clinical approach because such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. APPROACH AND
resultsHere, using zebrafish models of LPC-mediated liver regeneration, we present a proof of principle of such therapeutics by demonstrating a role for the epidermal growth factor receptor (EGFR) signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC-to-hepatocyte differentiation through the mitogen-activated ERK kinase (MEK)-extracellular signal-regulated kinase (ERK)-sex-determining region Y-box 9 (SOX9) cascade. Pharmacological inhibition of EGFR or MEK/ERK promoted LPC-to-hepatocyte differentiation as well as genetic suppression of the EGFR-ERK-SOX9 axis. Moreover, Sox9b overexpression in LPCs blocked their differentiation into hepatocytes. In the zebrafish liver injury model, both hepatocytes and biliary epithelial cells contributed to LPCs. EGFR inhibition promoted the differentiation of LPCs regardless of their origin. Notably, short-term treatment with EGFR inhibitors resulted in better liver recovery over the long term.
conclusionsThe EGFR-ERK-SOX9 axis suppresses LPC-to-hepatocyte differentiation during LPC-mediated liver regeneration. We suggest EGFR inhibitors as a proregenerative therapeutic drug for patients with advanced liver disease.
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