| Title | Direct chemical induction of hepatocyte-like cells with capacity for liver repopulation |
| Authors | Bai, Yunfei Yang, Zhenghao Xu, Xiaochan Ding, Wanqiu Qi, Juntian Liu, Feng Wang, Xiaoxiao Zhou, Bin Zhang, Wenpeng Zhuang, Xiaomei Li, Guanglu Zhao, Yang |
| Affiliation | Peking Univ, Beijing Key Lab Cardiometab Mol Med,Coll Future T, State Key Lab Nat & Biomimet Drugs,Ctr Life Sci,I, Minist Educ,Key Lab Cell Proliferat & Differentia, Beijing, Peoples R China Niels Bohr Inst, Copenhagen, Denmark Peking Univ, Coll Future Technol, Inst Mol Med, 5 Yi He Yuan Rd, Beijing 100871, Peoples R China Peking Univ, Peking Univ Peoples Hosp,Natl Clin Res Ctr Infect, Beijing Key Lab Hepatitis & Immunotherapy Liver D, Beijing Int Cooperat Base Sci & Technol NAFLD Dia, Beijing, Peoples R China Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai, Peoples R China Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing, Peoples R China |
| Keywords | MOUSE FIBROBLASTS DIRECT CONVERSION SOMATIC-CELLS PLURIPOTENCY DECADE |
| Issue Date | Aug-2022 |
| Publisher | HEPATOLOGY |
| Abstract | Background and Aims Cell fate can be directly reprogrammed from accessible cell types (e.g., fibroblasts) into functional cell types by exposure to small molecule stimuli. However, no chemical reprogramming method has been reported to date that successfully generates functional hepatocyte-like cells that can repopulate liver tissue, casting doubt over the feasibility of chemical reprogramming approaches to obtain desirable cell types for therapeutic applications. Approach and Results Here, through chemical induction of phenotypic plasticity, we provide a proof-of-concept demonstration of the direct chemical reprogramming of mouse fibroblasts into functional hepatocyte-like cells using exposure to small molecule cocktails in culture medium to successively stimulate endogenous expression of master transcription factors associated with hepatocyte development, such as hepatocyte nuclear factor 4a, nuclear receptor subfamily 1, group I, member 2, and nuclear receptor subfamily 1, group H, member 4. RNA sequencing analysis, metabolic assays, and in vivo physiological experiments show that chemically induced hepatocytes (CiHeps) exhibit comparable activity and function to primary hepatocytes, especially in liver repopulation to rescue liver failure in fumarylacetoacetate hydrolase(-/-)recombination activating gene 2(-/-)interleukin 2 receptor, gamma chain(-/-) mice in vivo. Single-cell RNA-seq further revealed that gastrointestinal-like and keratinocyte-like cells were induced along with CiHeps, resembling the activation of an intestinal program within hepatic reprogramming as described in transgenic approaches. Conclusions Our findings show that direct chemical reprogramming can generate hepatocyte-like cells with high-quality physiological properties, providing a paradigm for establishing hepatocyte identity in fibroblasts and demonstrating the potential for chemical reprogramming in organ/tissue repair and regeneration therapies. |
| URI | http://hdl.handle.net/20.500.11897/650567 |
| ISSN | 0270-9139 |
| DOI | 10.1002/hep.32686 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 天然药物与仿生药物国家重点实验室 细胞增殖分化调控机理研究教育部重点实验室 分子医学研究所 人民医院 |
