CCL2 supports human hepatocytes long-term expansion for bioartificial liver therapy to relieve acute liver failure and extrahepatic complications

The lack of expandable human hepatocytes in vitro hampers the clinical application of the bioartificial liver. Previous studies have shown that chemical cocktails containing growth factors can support long-term expansion of hepatocytes through dedifferentiation. Here, it is revealed that chemokine (C-C motif) ligand 2 (CCL2) is a key factor in liver regeneration. CCL2 could promote the long-term expansion (over 30 passages) of human primary hepatocytes and enhancing their proliferative efficiency. Subsequently, CCL2-mediated proliferation of hepatocytes can effectively expand in vitro, and repopulate the liver of Fah^-/- mice following 2-(2-nitro-4-trifluoromethylbenzyol)-1,3- cyclohexanedione (NTBC) withdrawal. Further studies revealed that CCL2-mediated hepatocyte proliferation could yield a sufficient number of highly active and well-functioning hepatocytes, crucial for supporting Bioartificial liver (BAL) therapy in treating acute liver failure (ALF) in a porcine model. Mechanically, BAL therapy effectively suppresses inflammatory responses, promotes liver regeneration, and subsequently protects extrahepatic organs, leading to improved survival rates in ALF porcine models.