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Volume 29, No 9, Sep 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 9, September 2019: 696-710   |  Open Access

ORIGINAL ARTICLES

A two-step lineage reprogramming strategy to generate functionally competent human hepatocytes from fibroblasts

Bingqing Xie 1,2, Da Sun 1,2, Yuanyuan Du1, Jun Jia1, Shicheng Sun 1, Jun Xu1, Yifang Liu3, Chengang Xiang1, Sitong Chen1,Huangfan Xie 1, Qiming Wang1, Guangya Li1, Xuehui LYU4, Hui Shen4, Shiyu Li4, Min Wu5, Xiaonan Zhang5, Yue Pu6, Kuanhui Xiang7,Weifeng Lai1, Peng Du4, Zhenghong Yuan8, Cheng Li3, Yan Shi1, Shichun Lu9 and Hongkui Deng 1,2

1School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China; 2State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China; 3Center for Bioinformatics, Peking University, Beijing 100871, China; 4MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; 5Shanghai Public Health Clinical Center, Shanghai 201508, China; 6Hangzhou Repugene Technology Co,. Ltd, Hangzhou, China; 7School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; 8Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai 200032, China and 9Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
 Correspondence: Yan Shi (shiyan@bjmu.edu.cn) or Shichun Lu (lsc620213@aliyun.com) or Hongkui Deng (hongkui_deng@pku.edu.cn)These authors contributed equally: Bingqing Xie, Da Sun, Yuanyuan Du

Terminally differentiated cells can be generated by lineage reprogramming, which is, however, hindered by incomplete conversion with residual initial cell identity and partial functionality. Here, we demonstrate a new reprogramming strategy by mimicking the natural regeneration route, which permits generating expandable hepatic progenitor cells and functionally competent human hepatocytes. Fibroblasts were first induced into human hepatic progenitor-like cells (hHPLCs), which could robustly expand in vitro and efficiently engraft in vivo. Moreover, hHPLCs could be efficiently induced into mature human hepatocytes (hiHeps) in vitro, whose molecular identity highly resembles primary human hepatocytes (PHHs). Most importantly, hiHeps could be generated in large quantity and were functionally competent to replace PHHs for drug-metabolism estimation, toxicity prediction and hepatitis B virus infection modeling. Our results highlight the advantages of the progenitor stage for successful lineage reprogramming. This strategy is promising for generating other mature human cell types by lineage reprogramming.


https://doi.org/10.1038/s41422-019-0196-x

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