Large-scale Generation of Functional and Transplantable Hepatocytes and Cholangiocytes from Human Endoderm Stem Cells
Sisi Feng, Jiaying Wu, Wei‐Lin Qiu, Yang Li, Xiaogang Deng, Ying Zhou, Yabin Chen, Li Xiao, Lei Yu, Hongsheng Li, Ziran Xu, Yini Xiao, Xiongzhao Ren, Ludi Zhang, Chenhua Wang, Zhen Sun, Jinglin Wang, Xiaoyan Ding, Yue‐Lei Chen, Paul Gadue, Guoyu Pan, Mina Ogawa, Shinichiro Ogawa, Jie Na, Peilin Zhang, Lijian Hui, Hao Yin, Luonan Chen, Cheng‐Ran Xu, Xin Cheng
Abstract
The ever-increasing therapeutic and pharmaceutical demand for liver cells calls for systems that enable mass production of hepatic cells. Here we describe a large-scale suspension system that uses human endoderm stem cells (hEnSCs) as precursors to generate functional and transplantable hepatocytes (E-heps) or cholangiocytes (E-chos). hEnSC-derived hepatic populations are characterized by single-cell transcriptomic analyses and compared with hESC-derived counterparts, in-vitro-maintained or -expanded primary hepatocytes and adult cells, which reveals that hepatic differentiation of hEnSCs recapitulates in vivo development and that the heterogeneities of the resultant populations can be manipulated by regulating the EGF and MAPK signaling pathways. Functional assessments demonstrate that E-heps and E-chos possess properties comparable with adult counterparts and that, when transplanted intraperitoneally, encapsulated E-heps were able to rescue rats with acute liver failure. Our study lays the foundation for cell-based therapeutic agents and in vitro applications for liver diseases.