Chemically induced revitalization of damaged hepatocytes for regenerative liver repair
Pengyan Lin,
Yunfei Bai,
Xinxin Nian,
Jun Chi,
Tianzhe Chen,
Jing Zhang,
Wenpeng Zhang,
Bin Zhou,
Yang Liu,
Yang Zhao
Affiliations
Pengyan Lin
State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Yunfei Bai
State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Xinxin Nian
Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China
Jun Chi
Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Tianzhe Chen
Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Jing Zhang
Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Wenpeng Zhang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
Bin Zhou
New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
Yang Liu
State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China
Yang Zhao
State Key Laboratory of Natural and Biomimetic Drugs, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China; Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China; Corresponding author
Summary: In prolonged liver injury, hepatocytes undergo partial identity loss with decreased regenerative capacity, resulting in liver failure. Here, we identified a five compound (5C) combination that could restore hepatocyte identity and reverse the damage-associated phenotype (e.g., dysfunction, senescence, epithelial to mesenchymal transition, growth arrest, and pro-inflammatory gene expression) in damaged hepatocytes (dHeps) from CCl4-induced mice with chronic liver injury, resembling a direct chemical reprogramming approach. Systemic administration of 5C in mice with chronic liver injury promoted hepatocyte regeneration, improved liver function, and ameliorated liver fibrosis. The hepatocyte-associated transcriptional networks were reestablished with chemical treatment as revealed by motif analysis of ATAC-seq, and a hepatocyte-enriched transcription factor, Foxa2, was found to be essential for hepatocyte revitalization. Overall, our findings indicate that the phenotype and transcriptional program of dHeps can be reprogrammed to generate functional and regenerative hepatocytes by using only small molecules, as an alternative approach to liver repair and regeneration.
