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Published April 2021 | Supplemental Material + Accepted Version
Journal Article Open

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

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.

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. We thank Kirsten Sadler for Tg(fabp10a:UHRF1-GFP), Alex Nechiporuk and Ken Poss for Tg(hsp70l:dnHRAS), Sarah Child for Tg(acta2:mCherry), and Anna Huttenlocher for Tg(mpeg1:Dendra2) fish. We also thank Jinrong Peng for anti-Bhmt and anti-p53 antibodies, Junsu Kang for the I-SceI destination vector, Paul Monga, Sucha Singh, and Jackie Russell for help in H&E staining, Neil Hukriede and Michael Tsang for discussion, and George Michalopoulos, Dean Yimlamai, Andy Duncan, and Angie Kim for critical reading of the manuscript. The work was supported by NIH grants to D.S. (DK101426, DK116993) and by the NIH/NIDDK Digestive Disease Research Core Center grant P30DK120531.

Attached Files

Accepted Version - nihms-1620505.pdf

Supplemental Material - hep31437-sup-0001-supinfo.docx

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Additional details

Created:
August 22, 2023
Modified:
December 22, 2023