ArticleThe Journal of clinical investigation2015
CCN1 induces hepatic ductular reaction through integrin αvβ₅-mediated activation of NF-κB.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 106 citations in OpenAlex.
- HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis.The Journal of clinical investigation · 2018Trial
- A subset of hepatic fibroblasts marked by Gli1 expression generates portal fibrosis and promotes ductular reaction.JHEP reports : innovation in hepatology · 2026Article
- Article
- A Novel 3D Visualization Method in Mice Identifies the Periportal Lamellar Complex (PLC) as a Key Regulator of Hepatic Ductal and Neuronal Branching Morphogenesis.bioRxiv : the preprint server for biology · 2026Article
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- CCN1-induced senescence and dysfunction of umbilical cord blood endothelial colony-forming cells in the pathogenesis of preeclampsia.Frontiers in endocrinology · 2026Article
- Macula Densa Alleviates Shiga Toxin-Induced Acute Kidney Injury via CCN1-Mediated Renal Tubular Repair.Toxins · 2025Article
- Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.Gastroenterology · 2025Review
- Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis.Frontiers in cell and developmental biology · 2025Review
- Macula densa cell angiogenic mechanisms and their therapeutic potential in kidney disease.Frontiers in bioengineering and biotechnology · 2025Article
- Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction.Cell proliferation · 2024Article
- CircHIPK2 Contributes Cell Growth in Intestinal Epithelial of Colitis and Colorectal Cancer through Promoting TAZ Translation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.Disease models & mechanisms · 2024Article
- Review
- Integrinβ-1 in disorders and cancers: molecular mechanisms and therapeutic targets.Cell communication and signaling : CCS · 2024Review
- JNKs protect from cholestatic liver disease progression by modulating Apelin signalling.JHEP reports : innovation in hepatology · 2023Article
- Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis.Science translational medicine · 2023Article
- Structural insights into regulation of CCN protein activities and functions.Journal of cell communication and signaling · 2023Review
- Significance of CCNs in liver regeneration.Journal of cell communication and signaling · 2023Review
- Identification of acquired Notch3 dependency in metastatic Head and Neck Cancer.Communications biology · 2023Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Liver cholestatic diseases, which stem from diverse etiologies, result in liver toxicity and fibrosis and may progress to cirrhosis and liver failure. We show that CCN1 (also known as CYR61), a matricellular protein that dampens and resolves liver fibrosis, also mediates cholangiocyte proliferation and ductular reaction, which are repair responses to cholestatic injury. In cholangiocytes, CCN1 activated NF-κB through integrin αvβ5/αvβ3, leading to Jag1 expression, JAG1/NOTCH signaling, and cholangiocyte proliferation. CCN1 also induced Jag1 expression in hepatic stellate cells, whereupon they interacted with hepatic progenitor cells to promote their differentiation into cholangiocytes. Administration of CCN1 protein or soluble JAG1 induced cholangiocyte proliferation in mice, which was blocked by inhibitors of NF-κB or NOTCH signaling. Knock-in mice expressing a CCN1 mutant that is unable to bind αvβ5/αvβ3 were impaired in ductular reaction, leading to massive hepatic necrosis and mortality after bile duct ligation (BDL), whereas treatment of these mice with soluble JAG1 rescued ductular reaction and reduced hepatic necrosis and mortality. Blockade of integrin αvβ5/αvβ3, NF-κB, or NOTCH signaling in WT mice also resulted in defective ductular reaction after BDL. These findings demonstrate that CCN1 induces cholangiocyte proliferation and ductular reaction and identify CCN1/αvβ5/NF-κB/JAG1 as a critical axis for biliary injury repair.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.