Chemically Derived Hepatic Progenitors Are Reprogrammed through Autophagy Suppression by A83-01

Abstract

Human chemically derived hepatic progenitors (hCdHs) reprogrammed using three chemicals—HGF, A83-01, and CHIR99021 (collectively denoted as “HAC”)—have been suggested as a novel therapeutic for patients with severe liver diseases in our previous study. Despite its high proliferation and re-differentiation ability into functional hepatocytes, the reprogramming mechanism of hCdHs remained unknown. Recently, it has been reported that autophagy, a self-degradation process, is responsible for stem cell metabolism. In this study, we investigated whether autophagy regulates the generation mechanism of CdHs, mainly using hepatocytes from C57BL/6 mice, with additional analysis using human hepatocytes. As a result, we found that autophagy flux is inhibited during the generation of mouse CdHs (mCdHs) by A83-01, which is compensated by CHIR99021. Moreover, the suppression of autophagy by bafilomycin A1 enhanced the proliferation ability of mCdHs during the generation process. hCdHs also showed a similar autophagy inhibition pattern to mCdHs during the generation process. Taken together, our study indicates that autophagy is downregulated during the generation of CdHs, promoting their proliferation. This may contribute to the production of hCdHs with stable productivity, which may serve as a therapeutic for severe liver diseases.