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

doi:10.1016/j.isci.2023.108532

Chemically induced revitalization of damaged hepatocytes for regenerative liver repair

iScience. 2023 Nov 23;26(12):108532. doi: 10.1016/j.isci.2023.108532. eCollection 2023 Dec 15.

Authors

Pengyan Lin^{1

2}, Yunfei Bai^{1

2}, Xinxin Nian³, Jun Chi², Tianzhe Chen², Jing Zhang², Wenpeng Zhang⁴, Bin Zhou⁵, Yang Liu^{1

2}, Yang Zhao^{1

2

3}

Affiliations

¹ 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.
² Plastech Pharmaceutical Technology Co., Ltd, Nanjing 210043, China.
³ Peking-Tsinghua Center for Life Science, Peking University, Beijing 100871, China.
⁴ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
⁵ 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.

Abstract

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.

Keywords: Biological sciences; Cell revitalization; Chemical compounds; Chronic liver injury; Liver regeneration; Natural sciences; Pharmacology; Physiology.