Liver Failure and Engineering Liver Regeneration

Liver failure is a life-threatening syndrome characterized by multiorgan failure and high short-term mortality rates. Liver transplantation is an effective therapy but is limited by the shortage of donor organs. Liver tissue engineering has significantly progressed in engineering cells, biomaterials and tissue architectures to fabricate transplantable liver tissue or bioengineered whole liver over the last decades. Functional bioengineered liver has been recognized as a promising alternative to orthotopic liver transplantation. However, how to biofabricate an integrated vascular and biliary network with three-dimensional microstructure is the first challenge in development of bioengineered transplantable livers. We have previously developed vascularized liver organoids and functional ductal organoids in decellularized liver scaffold (DLS) of rats. The results indicated that myosin-binding protein C1 (MYPC1) enhanced the integrity of the vascular barrier structure mediated by VE-cadherin and regulation of the cytoskeleton, and Delta-like ligand 4 (DLL4) participated in the liver regeneration through remodeling injured bile ducts. Based on above results, we developed a new bioengineered liver with integrated vascular and biliary network using rat DLS. The biological processes at different time points identified with proteomics revealed development characteristics of vascularization in bioengineered liver, and at least 14 days of in vitro

culture should be recommended for developing a functionalized vascular structure. The new developed functional ductal organoids with biliary tree networks were stable for functional long-term culture, providing a basis for further elucidation of the mechanism in bile duct remodeling by dynamically revealing metabolic signatures. We also first performed an orthotopic transplantation of bioengineered livers in rats subjected to complete hepatectomy. The transplanted bioengineered livers can prolong the survival of rats subjected to complete hepatectomy.

Dr. Jun Li, MD & Ph.D is a “Qiushi” Distinguished Professor and Doctoral Supervisor at Zhejiang University, as well as the Vice Director of the State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases at The First Affiliated Hospital, Zhejiang University School of Medicine.

Dr. Li has long focused on developing novel technologies for diagnosing and treating liver failure. He established the Chinese diagnostic criteria for HBV-ACLF (COSSH-ACLF) and an early prognostic model systems for liver failure in Chinese hepatitis B patients, which have been adopted into clinical guidelines by the AASLD, EASL and APASL. He proposed and validated the theory that “HBV activation-induced immune-metabolic imbalance is the core mechanism of hepatitis B-related liver failure,” paving the way for precision treatments targeting immunometabolism. His pioneering work includes using human bone marrow mesenchymal stem cell transplantation to rescue fulminant liver failure, developing the first dual humanized mouse model with hepatocytes and immune cells from a single stem cell source, and creating the first naturally HBV-infected cirrhotic mouse model. He also led groundbreaking studies on the in-situ transplantation of recellularized liver-like organs in rats using decellularized whole-liver scaffolds.

As a principal investigator, he has led 20 national projects, including grants from the CNSF and the National S&T Major Project of China. He has published over 100 SCI papers in journals such as Nat Rev GH, Gut, J Hepatol, and Hepatology.