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Large-Scale Generation of Functional and Transplantable Hepatocytes and Cholangiocytes from Human Endoderm Stem Cells

110 Pages Posted: 3 May 2019 Sneak Peek Status: Review Complete

See all articles by Sisi Feng

Sisi Feng

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Jiaying Wu

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Li Yang

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

Xiaogang Deng

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Wei-Lin Qiu

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

Ying Zhou

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Yabin Chen

ShanghaiTech University - School of Life Science and Technology

Xiao Li

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Lei Yu

Fudan University - Department of Liver Surgery and Transplantation

Tianlong Fu

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Xiongzhao Ren

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Ludi Zhang

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Paul Gadue

University of Pennsylvania - Department of Pathology and Lab Medicine

Guoyu Pan

Chinese Academy of Sciences (CAS) - State Key Laboratory of Drug Research

Mina Ogawa

McEwen Centre for Regenerative Medicine

Shinichiro Ogawa

McEwen Centre for Regenerative Medicine

Jie Na

Tsinghua University - Center for Stem Cell Biology and Regenerative Medicine

Lijian Hui

Fudan University - Department of Liver Surgery and Transplantation

Cheng-Ran Xu

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

Luonan Chen

Chinese Academy of Sciences (CAS) - Key Laboratory of Systems Biology; Chinese Academy of Sciences (CAS) - Center for Excellence in Animal Evolution and Genetics; ShanghaiTech University - School of Life Science and Technology; Chinese Academy of Sciences (CAS) - Research Center for Brain-Inspired Intelligence

Xi Chen

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

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Abstract

The ever-increasing therapeutic and pharmaceutical demands for liver cells and tissues call for mass production systems that enable efficient in vitro generation of hepatic cell lineages. Here, we describe the use of human endoderm stem cells (EnSCs) as precursors for generating hepatoblasts, as well as functionally mature and transplantable hepatocytes or cholangiocytes in a large-scale serum-free 3D differentiation system. Single-cell transcriptomic analysis is used as a tool to characterize the hepatic populations and guide improvements to the protocol. We demonstrate that the hepatic differentiation of EnSCs recapitulates the in vivo developmental trajectory and find that the regulation of the EGF and MAPK signaling pathways is important for proper lineage progression for the generation of functionally mature hepatocytes or cholangiocytes. When transplanted into liver disease animal models, the resultant hepatocytes are able to rescue the animals and repopulate the host livers. The establishment of this large-scale system for hepatic differentiation of EnSCs lays the foundation for cell-based therapeutic applications for liver diseases and for in vitro liver reconstruction.

Keywords: Human endoderm stem cells, cell fate, cell differentiation, large scale system, liver development, single-cell RNA-sequencing, EGF signaling pathway, MAPK signaling pathway

Suggested Citation

Feng, Sisi and Wu, Jiaying and Yang, Li and Deng, Xiaogang and Qiu, Wei-Lin and Zhou, Ying and Chen, Yabin and Li, Xiao and Yu, Lei and Fu, Tianlong and Ren, Xiongzhao and Zhang, Ludi and Gadue, Paul and Pan, Guoyu and Ogawa, Mina and Ogawa, Shinichiro and Na, Jie and Hui, Lijian and Xu, Cheng-Ran and Chen, Luonan and Chen, Xi, Large-Scale Generation of Functional and Transplantable Hepatocytes and Cholangiocytes from Human Endoderm Stem Cells (April 26, 2019). CELL-STEM-CELL-D-19-00247. Available at SSRN: https://ssrn.com/abstract=3378283 or http://dx.doi.org/10.2139/ssrn.3378283
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sisi Feng

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology ( email )

320 Yue Yang Road
Shanghai, 200031
China

Jiaying Wu

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Shanghai
China

Li Yang (Contact Author)

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

Beijing, 10087
China

Xiaogang Deng

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

320 Yue Yang Road
Shanghai, 200031
China

Wei-Lin Qiu

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation

Beijing, 10087
China

Ying Zhou

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

320 Yue Yang Road
Shanghai, 200031
China

Yabin Chen

ShanghaiTech University - School of Life Science and Technology

100 Haike Road, Zhangjiang Hi-Tech Park, Pudong
Research Building
Shanghai, 201210
China

Xiao Li

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

320 Yue Yang Road
Shanghai, 200031
China

Lei Yu

Fudan University - Department of Liver Surgery and Transplantation

Shanghai
China

Tianlong Fu

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Shanghai
China

Xiongzhao Ren

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Shanghai
China

Ludi Zhang

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology

Shanghai
China

Paul Gadue

University of Pennsylvania - Department of Pathology and Lab Medicine

Philadelphia, PA 19104
United States

Guoyu Pan

Chinese Academy of Sciences (CAS) - State Key Laboratory of Drug Research

52 Sanlihe Rd.
Datun Road, Anwai
Beijing, Xicheng District 100864
China

Mina Ogawa

McEwen Centre for Regenerative Medicine

MaRS Centre, Toronto Medical Discovery Tower
101 College St. 8th Floor, room 701
Toronto, ON M5G 1L7
Canada

Shinichiro Ogawa

McEwen Centre for Regenerative Medicine

MaRS Centre, Toronto Medical Discovery Tower
101 College St. 8th Floor, room 701
Toronto, ON M5G 1L7
Canada

Jie Na

Tsinghua University - Center for Stem Cell Biology and Regenerative Medicine

Beijing, 100084
China

Lijian Hui

Fudan University - Department of Liver Surgery and Transplantation

Shanghai
China

Cheng-Ran Xu

Peking University - Ministry of Education Key Laboratory of Cell Proliferation and Differentiation ( email )

Beijing, 10087
China

Luonan Chen

Chinese Academy of Sciences (CAS) - Key Laboratory of Systems Biology ( email )

Shanghai, 200031
China

Chinese Academy of Sciences (CAS) - Center for Excellence in Animal Evolution and Genetics ( email )

Kunming
China

ShanghaiTech University - School of Life Science and Technology ( email )

100 Haike Road, Zhangjiang Hi-Tech Park, Pudong
Research Building
Shanghai, 201210
China

Chinese Academy of Sciences (CAS) - Research Center for Brain-Inspired Intelligence ( email )

China

Xi Chen

Chinese Academy of Sciences (CAS) - State Key Laboratory of Cell Biology ( email )

320 Yue Yang Road
Shanghai, 200031
China

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