Hepatocyte transplantation has many potential applications. Extensive animal experiments have shown that hepatocytes transplanted in the liver or at ectopic sites survive, function, and actively participate in the regenerative process. However our understanding of hepatocyte engraftment and their remarkable proliferative and regenerative potential is limited, even if primary hepatocyte transplantation is at the doorstep of applications in the treatment of inherited and acquired human diseases. We previously made a serendipitous observation that normal hepatocytes transplanted in the peritoneal cavity of an animal with lethal liver disease migrate into the lymphatic system and engineer ectopic liver-like organoids that rescue an animal model from a fatal metabolic disorder. How hepatocytes enter the lymphatics and what molecular mechanism is responsible for the generation of ectopic mass is not known. We hypothesized that hepatocytes must borrow some of the molecular mechanism lymphocytes use to migrate into the lymphatics. Our interest will be to study ectopic cell transplantation and our central objective of our application is to translate a highly interesting observation, the generation of ectopic liver, to a potential clinical application for patients with liver diseases.
We are proposing a transformative approach by exploiting hepatocyte engraftment and growth in milky spots as a model to understand ectopic liver organogenesis. Our central hypothesis is that hepatocytes employed similar molecular mechanisms used by lymphocytes in lymphatic sites, or by tumor cells during peritoneal metastases, and we speculate that the identification of these molecular mechanisms will define the hepatic microenvironment necessary for peritoneal liver organogenesis. Upon completion, our proposal will have outlined new mechanisms used by hepatocytes to generate ectopic liver organogenesis.
