ABSTRACT
Background: The remarkable ability of the liver to regenerate by proliferation of mature hepatocytes constitutes the first mechanism of repair commonly named the hepatocyte-driven regeneration. Yet, during chronic liver injury or acute severe hepatocyte death, proliferation of hepatocytes becomes exhausted. In these cases, alternative cholangiocyte-driven regeneration occurs during which cholangiocytes differentiate into healthy hepatocytes. Despite these two mechanisms of repair, end stage liver disease remains the 12th most common cause of death in the US, begging for therapeutic strategies to harness intrinsic mechanisms of regeneration. My lab investigates various strategies using nucleoside-modified mRNA complexed in lipid nanoparticles (mRNA-LNP) to harness hepatocyte-and cholangiocyte-driven liver repair to treat acute and chronic liver disease mouse models. Method(s): We recently pioneered mRNA-LNP as a technology to deliver regenerative factors to the liver for liver regeneration application, departing from the original protein replacement or immunization applications whose safety is widely validated with the current mRNA-based COVID-19 vaccines. Acute and chronic liver diseases were recapitulated in mice with the single dose of acetaminophen (APAP) overdose model and the choline-deficient ethioninesupplemented (CDE) diet, respectively. Mice were also injected with AAV8-Tbg-p21 prior to liver injury to mimic hepatocyte senescence. Result(s): We demonstrate that delivery via mRNA-LNP to the liver of the known key hepatocyte mitogen hepatocyte growth factor (HGF) and epidermal growth factor (EGF) enhances hepatocyte-driven repair by sharply reversing steatosis and accelerating restoration of liver function in the CDE chronic model, while accelerating liver regeneration in APAP acute model with rapid return to baseline serum ALT levels. Interestingly, the overlooked factor, growth hormone, delivered with mRNA-LNP significantly accelerates liver repair after APAP overdose. To harness cholangiocyte-driven repair, we delivered VEGFA in acute and chronic injured mouse livers. We found that VEGFA mRNA-LNP induces robust cholangiocyte conversion to hepatocytes, and importantly, reverts steatosis and fibrosis. Conclusion(s): Our study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness both hepatocyte-and cholangiocyte-driven liver regeneration to ultimately treat human acute and chronic liver diseases.