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
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...
November 20, 2023: Cell Stem Cell