CaltechAUTHORS
  A Caltech Library Service

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

So, Juhoon and Kim, Minwook and Lee, Seung‐Hoon and Ko, Sungjin and Lee, Daniel A. and Park, Hyewon and Azuma, Mizuki and Parsons, Michael J. and Prober, David and Shin, Donghun (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. Hepatology, 73 (4). pp. 1494-1508. ISSN 0270-9139. PMCID PMC7769917. doi:10.1002/hep.31437. https://resolver.caltech.edu/CaltechAUTHORS:20200630-132041344

[img] MS Word - Supplemental Material
See Usage Policy.

14MB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20200630-132041344

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/hep.31437DOIArticle
ORCID:
AuthorORCID
Lee, Daniel A.0000-0001-7411-2740
Prober, David0000-0002-7371-4675
Alternate Title:Attenuating the EGFR-ERK-SOX9 axis promotes liver progenitor cell‐mediated liver regeneration in zebrafish
Additional Information:© 2020 by the American Association for the Study of Liver Diseases. Issue Online: 13 April 2021; Version of Record online: 13 April 2021; Accepted manuscript online: 29 June 2020; Manuscript accepted: 03 June 2020; Manuscript revised: 02 June 2020; Manuscript received: 13 December 2019. Supported by NIH grants to D.S. (DK101426, DK116993) and by the NIH/NIDDK Digestive Disease Research Core Center grant P30DK120531. Potential conflict of interest: Nothing to report.
Funders:
Funding AgencyGrant Number
NIHDK101426
NIHDK116993
NIHP30DK120531
Subject Keywords:reprogramming; liver progenitor cells; oval cells; biliary epithelial cells; sox9b
Issue or Number:4
PubMed Central ID:PMC7769917
DOI:10.1002/hep.31437
Record Number:CaltechAUTHORS:20200630-132041344
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200630-132041344
Official Citation:So, J., Kim, M., Lee, S.‐H., Ko, S., Lee, D.A., Park, H., Azuma, M., Parsons, M.J., Prober, D. and Shin, D. (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. Hepatology, 73: 1494-1508. https://doi.org/10.1002/hep.31437
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104166
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jun 2020 21:01
Last Modified:23 Apr 2021 22:34

Repository Staff Only: item control page