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Cell Res. 2019 Dec;29(12):1009-1026. doi: 10.1038/s41422-019-0242-8. Epub 2019 Oct 18.

Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury.

Wang S1,2, Wang X1,3, Tan Z1, Su Y1, Liu J1,4, Chang M1, Yan F1, Chen J5, Chen T5, Li C6, Hu J3, Wang Y7,8.

Author information

1
Tissue Engineering and Regenerative Medicine Lab, Beijing Institute of Health Service and Transfusion Medicine, 100850, Beijing, China.
2
Army Tuberculosis Prevention and Control Key Laboratory, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, The 8th Medical Center of Chinese PLA General Hospital, 100091, Beijing, China.
3
Department of Nursing, Hebei Medical University, 050017, Shijiazhuang, China.
4
Hepatal-Biliary-Pancreatic Center, Translational Research Center, Beijing Tsinghua Chang Gung Hospital, 102218, Beijing, China.
5
Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510289, Guangzhou, China.
6
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
7
Tissue Engineering and Regenerative Medicine Lab, Beijing Institute of Health Service and Transfusion Medicine, 100850, Beijing, China. wangyf1972@gmail.com.
8
Hepatal-Biliary-Pancreatic Center, Translational Research Center, Beijing Tsinghua Chang Gung Hospital, 102218, Beijing, China. wangyf1972@gmail.com.

Abstract

We report the generation of human ESC-derived, expandable hepatic organoids (hEHOs) using our newly established method with wholly defined (serum-free, feeder free) media. The hEHOs stably maintain phenotypic features of bipotential liver stem/progenitor cells that can differentiate into functional hepatocytes or cholangiocytes. The hEHOs can expand for 20 passages enabling large scale expansion to cell numbers requisite for industry or clinical programs. The cells from hEHOs display remarkable repopulation capacity in injured livers of FRG mice following transplantation, and they differentiate in vivo into mature hepatocytes. If implanted into the epididymal fat pads of immune-deficient mice, they do not generate non-hepatic lineages and have no tendency to form teratomas. We further develop a derivative model by incorporating human fetal liver mesenchymal cells (hFLMCs) into the hEHOs, referred to as hFLMC/hEHO, which can model alcoholic liver disease-associated pathophysiologic changes, including oxidative stress generation, steatosis, inflammatory mediators release and fibrosis, under ethanol treatment. Our work demonstrates that the hEHOs have considerable potential to be a novel, ex vivo pathophysiological model for studying alcoholic liver disease as well as a promising cellular source for treating human liver diseases.

PMID:
31628434
DOI:
10.1038/s41422-019-0242-8

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