ArticleGastroenterology2019
Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.
Article in Gastroenterology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 86 citations in OpenAlex.
- Retrorsine impairs liver regeneration by inducing progenitor cell-senescenceAnnals of medicine · 2026Article
- Urea cycle dysregulation and arginine pathways in the pathogenesis of NAFLD and NASH (Review).International journal of molecular medicine · 2026Review
- Massive hepatic necrosis-associated acute liver failure.eGastroenterology · 2026Review
- Liver oval cells in response to HDAC1 inhibitor trichostatin A: immunohistochemical characterization using OV-6 hepatic expression.Anatomy & cell biology · 2025Article
- Review
- Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish.Nature communications · 2025Article
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Protein modifications in hepatic ischemia-reperfusion injury: molecular mechanisms and targeted therapy.Frontiers in immunology · 2025Review
- Chemically Defined Organoid Culture System for Cholangiocyte Differentiation.Advanced healthcare materials · 2024Article
- HDAC1: a promising target for cancer treatment: insights from a thorough analysis of tumor functions.Translational cancer research · 2024Article
- Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations.Clinical and translational medicine · 2024Review
- Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases.Genes & diseases · 2024Review
- Zebrafish-A Suitable Model for Rapid Translation of Effective Therapies for Pediatric Cancers.Cancers · 2024Review
- Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead.Acta pharmaceutica Sinica. B · 2024Review
- Using different zebrafish models to explore liver regeneration.Frontiers in cell and developmental biology · 2024Review
- Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates.International journal of biological sciences · 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
- LSD1 promotes the egress of hematopoietic stem and progenitor cells into the bloodstream during the endothelial-to-hematopoietic transition.Developmental biology · 2023Article
- The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway.NPJ Regenerative medicine · 2023Article
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Authors and funding
15 authors at 6 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsUpon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms.
methodsWe used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of β-catenin (Ctnnb1
resultsLoss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of β-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis.
conclusionsHdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.
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