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The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Fatima Rizvi, Yu-Ri Lee, Ricardo Diaz-Aragon, Pushpinder S Bawa, Juhoon So, Rodrigo M Florentino, Susan Wu, Arianna Sarjoo, Emily Truong, Anna R Smith, Feiya Wang, Elissa Everton, Alina Ostrowska, Kyounghwa Jung, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Alejandro Soto-Gutierrez, Donghun Shin, Valerie Gouon-Evans. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell stem cell. 2023 Dec 07;30(12):1640-1657.e8

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PMID: 38029740

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