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

作　　者：Shuyong Wang Xuan Wang Zuolong Tan Yuxin Su Juan Liu Mingyang Chang Fang Yan Jie Chen Tao Chen Chuanjiang Li Jie Hu Yunfang Wang 

机构地区：[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

出　　处：《Cell Research》2019年第12期1009-1026,共18页细胞研究（英文版）

基　　金：the National Natural Science Foundations of China(No.81730052);the Interdisciplinary Cooperation Project of Beijing Nova Program(Z1811100006218127);the National Major Scientific and Technological Special Project for"Significant New Drugs Development"(2018ZX09711003-001-002);the National Key Research and Development Program of China(No.2016YFC1101305);the Science and Technology Planning Project of Guangdong China(2015A050502023);the Guangdong Province Science and Technology Program(2018KJYZ021);Science and Technology Program of Guangzhou,China(STPG;2016201604030054).

摘　　要：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.

关 键 词：HEPATIC enable MAINTAIN 

分 类 号：R57[医药卫生—消化系统]