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Attenuating the EGFR-ERK-SOX9 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 (2020) Attenuating the EGFR-ERK-SOX9 axis promotes liver progenitor cell‐mediated liver regeneration in zebrafish. Hepatology . ISSN 0270-9139. (In Press)

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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 pro‐inflammatory 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 since such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. Here, using zebrafish models of LPC‐mediated liver regeneration, we present a proof‐of‐principle of such therapeutics by demonstrating a role for the EGFR signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC‐to‐hepatocyte differentiation via the MEK‐ERK‐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. Conclusion: The EGFR‐ERK‐SOX9 axis suppresses LPC‐to‐hepatocyte differentiation during LPC‐mediated liver regeneration. We suggest EGFR inhibitors as a pro‐regenerative therapeutic drug for patients with advanced liver disease.

Item Type:Article
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Lee, Daniel A.0000-0001-7411-2740
Prober, David0000-0002-7371-4675
Additional Information:© 2020 Wiley. Accepted manuscript online: 29 June 2020.
Subject Keywords:reprogramming; liver progenitor cells; oval cells; biliary epithelial cells; sox9b
Record Number:CaltechAUTHORS:20200630-132041344
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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. (2020), Attenuating the EGFR‐ERK‐SOX9 axis promotes liver progenitor cell‐mediated liver regeneration in zebrafish. Hepatology. Accepted Author Manuscript. doi: 10.1002/hep.31437
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104166
Deposited By: Tony Diaz
Deposited On:30 Jun 2020 21:01
Last Modified:30 Jun 2020 21:01

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