Introduction: Liver transplantation is the preferred treatment for end-stage liver disease, but donor scarcity limits its efficacy. High expectations for regenerative medicine exist as an alternative curative treatment to liver transplantation. Human hepatocyte transplantation is being explored as an alternative, yet challenges like limited proliferation and cell sources persist. Recently, a promising avenue has emerged with the development of chemically induced liver progenitor cells (CLiP) with bidirectional differentiation potential.
Methods: Our coinvestigator, Ochiya et al., utilized three small molecule cocktails (Rock inhibitor, TGF-beta inhibitor, and GSK3 inhibitor, YAC) to convert rodent mature hepatocytes into CLiP resembling endogenous liver progenitor cells (Katsuda, Ochiya et al. Cell Stem Cell 2017). CLiP are easily cultured in vitro and have demonstrated significant potential for liver regeneration upon transplantation, offering promise for replacing impaired livers.
Result: We have previously demonstrated that transplantation of rat CLiP into a mouse model of diet-induced NASH suppressed liver fibrosis (Murakami, Eguchi, et al. Regen Ther 2022) and induction of human CLiP (hCLiP) from hepatocytes sourced from patients with advanced cirrhosis (Child-Pugh B or C) (Miyoshi, Eguchi et al. J Gastroenterol 2022). The hCLiP could form the bile duct system (Li, Eguchi, et al. Front. Bioeng. Biotechnol 2023) and hepatobiliary organoids in vitro. Furthermore, hCLiP could differentiate into bile duct epithelial cells and mature hepatocytes and reduce bile duct reaction in a bile duct transection model. The efficacy of hCLiP from cirrhosis tissue against NASH in a mice model was also confirmed (Miyamoto, Eguchi et al. Cell Transplant. Revised). Currently, we are also conducting autologous CLiP transplantation experiment in a NAFLD porcine model as a preclinical study and have confirmed favorable therapeutic effects.
Conclusion: These findings suggest CLiP transplantation holds promise for treating liver disease. Improving engraftment rates and therapeutic efficacy is crucial for practical human application.