論文 - 詳細
| RRC ID | 70310 |
|---|---|
| 著者 | So J, Kim M, Lee SH, Ko S, Lee DA, Park H, Azuma M, Parsons MJ, Prober D, Shin D. |
| タイトル | 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. |
| ジャーナル | Hepatology |
| Abstract |
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. |
| 巻・号 | 73(4) |
| ページ | 1494-1508 |
| 公開日 | 2021-4-1 |
| DOI | 10.1002/hep.31437 |
| PMID | 32602149 |
| PMC | PMC7769917 |
| MeSH | Animals Animals, Genetically Modified Butadienes / pharmacology Cell Differentiation / drug effects Enzyme Inhibitors / pharmacology ErbB Receptors / antagonists & inhibitors ErbB Receptors / metabolism* Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases / metabolism* Hepatocytes / cytology Liver Regeneration / drug effects* MAP Kinase Signaling System / drug effects* Nitriles / pharmacology Quinazolines / pharmacology SOX9 Transcription Factor / metabolism* Stem Cells / cytology Stem Cells / metabolism* Tyrphostins / pharmacology Zebrafish / metabolism* |
| IF | 14.679 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(6xTcf/LefBS-miniP:d2EGFP)isi01 |