PMID- 32602149 OWN - NLM STAT- MEDLINE DCOM- 20211026 LR - 20220402 IS - 1527-3350 (Electronic) IS - 0270-9139 (Print) IS - 0270-9139 (Linking) VI - 73 IP - 4 DP - 2021 Apr TI - 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. PG - 1494-1508 LID - 10.1002/hep.31437 [doi] AB - BACKGROUND AND AIMS: The 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 RESULTS: Here, 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. CONCLUSIONS: The 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. CI - (c) 2020 by the American Association for the Study of Liver Diseases. FAU - So, Juhoon AU - So J AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Kim, Minwook AU - Kim M AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Lee, Seung-Hoon AU - Lee SH AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Ko, Sungjin AU - Ko S AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Lee, Daniel A AU - Lee DA AUID- ORCID: 0000-0001-7411-2740 AD - Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA. FAU - Park, Hyewon AU - Park H AD - Department of Molecular Biosciences, University of Kansas, Lawrence, KS. FAU - Azuma, Mizuki AU - Azuma M AD - Department of Molecular Biosciences, University of Kansas, Lawrence, KS. FAU - Parsons, Michael J AU - Parsons MJ AD - Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA. FAU - Prober, David AU - Prober D AD - Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA. FAU - Shin, Donghun AU - Shin D AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. LA - eng GR - R01 DK116993/DK/NIDDK NIH HHS/United States GR - P30 DK120531/DK/NIDDK NIH HHS/United States GR - R01 NS070911/NS/NINDS NIH HHS/United States GR - R01 DK101426/DK/NIDDK NIH HHS/United States GR - R01 DK080730/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Butadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Nitriles) RN - 0 (Quinazolines) RN - 0 (SOX9 Transcription Factor) RN - 0 (Tyrphostins) RN - 0 (U 0126) RN - 170449-18-0 (RTKI cpd) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Butadienes/pharmacology MH - Cell Differentiation/drug effects MH - Enzyme Inhibitors/pharmacology MH - ErbB Receptors/antagonists & inhibitors/*metabolism MH - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/*metabolism MH - Hepatocytes/cytology MH - Liver Regeneration/*drug effects MH - MAP Kinase Signaling System/*drug effects MH - Nitriles/pharmacology MH - Quinazolines/pharmacology MH - SOX9 Transcription Factor/*metabolism MH - Stem Cells/cytology/*metabolism MH - Tyrphostins/pharmacology MH - Zebrafish/*metabolism PMC - PMC7769917 MID - NIHMS1620505 EDAT- 2020/07/01 06:00 MHDA- 2021/10/27 06:00 PMCR- 2022/04/01 CRDT- 2020/07/01 06:00 PHST- 2020/06/02 00:00 [revised] PHST- 2019/12/13 00:00 [received] PHST- 2020/06/03 00:00 [accepted] PHST- 2020/07/01 06:00 [pubmed] PHST- 2021/10/27 06:00 [medline] PHST- 2020/07/01 06:00 [entrez] PHST- 2022/04/01 00:00 [pmc-release] AID - 10.1002/hep.31437 [doi] PST - ppublish SO - Hepatology. 2021 Apr;73(4):1494-1508. doi: 10.1002/hep.31437.