HuLiver

Mass-production of high-quality human hepatocytes is at the heart of an economic challenge, biotechnology and biomedical research. Indeed, the liver is the major organ for the destruction and elimination of endogenous metabolic wastes and xenobiotics (pollutants, pesticides, medical drugs). It is responsible for the metabolism of many drugs into active metabolites. However, these active metabolites, or their intermediates may induce liver toxicity. Unexpected problems of toxicity and pharmacokinetics are responsible for most failures in clinical drug development. The liver performs other vital functions such as the production of most of the serum proteins and lipids, bile production, the metabolism of food into nutrients, and glucose homeostasis (storage). Finally, it is the target organ of human specific infectious agents, such as Hepatitis C virus. Thus, there is a major interest of biopharmaceutical industries, scientists and clinicians for having human hepatocytes on demand. Studies on animal models can be misleading because the activity, specificity and intermediate metabolites produced by liver enzymes are often different from their human counterparts. Hepatocytes isolated from human liver biopsies represent the ideal source, but availability of liver biopsies is limited and hepatocytes cannot be amplified in vitro. Liver organs that are not suitable for organ transplantation are scarce and of poor quality (massive steatosis in general). This project associates the INSERM UMR 1064 unit (Nantes) and the society Biopredic (Rennes). The UMR1064 Center of Research in Transplantation and Immunology, develops a research area focuses on the induction of tolerance in transplantation and cell therapy in the Liver. Biopredic is an internationally recognized company specializing in the distribution of primary human cells and in particular human hepatocytes for research, drug development, pharmacology and toxicology. The LabCom program aims to develop a robust and reliable system capable to mass-produce human hepatocytes. The liver has an extraordinary ability to regenerate after injury and unique feature to regenerate from residual hepatocytes present in the liver. Currently, it is not possible to reconstruct in vitro the complex architecture of the liver organ capable of replicating hepatocytes. We will develop an innovative technology based on liver regeneration properties to produce rapidly and massively human hepatocytes in vivo in the rat liver, which has the ideal size as a laboratory bioreactor (1 billion hepatocytes per liver). We will develop a method for the purification of human hepatocytes from humanized livers. We will build large cell banks of cryopreserved human hepatocytes of different genotypes ready for commercialization. In addition, a second innovation of the developed technology is to provide an animal model with a humanized liver capable of modeling human liver fibrosis/ cirrhosis and respond to vaccination. Biopredic company will enrich their intellectual properties and its technological know-how, allowing it to be innovative and become a leadership in the industrial environment of a strong international competition. INSERM UMR1064 will economically develop its know-how and have a humanized liver model in rats for its research in immunology of transplantation and liver biotherapy.