Direct Reprogramming of Human Fibroblasts to Functional and Expandable Hepatocytes

被引：474

作者：

Huang, Pengyu ^{[1
]}

Zhang, Ludi ^{[1
]}

Gao, Yimeng ^{[1
]}

He, Zhiying ^{[2
]}

Yao, Dan ^{[3
]}

Wu, Zhitao ^{[3
]}

Cen, Jin ^{[1
]}

Chen, Xiaotao ^{[1
]}

Liu, Changcheng ^{[2
]}

Hu, Yiping ^{[2
]}

Lai, Dongmei ^{[4
]}

Hu, Zhenlei ^{[5
]}

Chen, Li ^{[6
]}

Zhang, Ying ^{[6
]}

Cheng, Xin ^{[1
]}

Ma, Xiaojun ^{[6
]}

Pan, Guoyu ^{[3
]}

Wang, Xin ^{[7
,8
,9
]}

Hui, Lijian ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China

[2] Second Mil Med Univ, Dept Cell Biol, Shanghai 200433, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Int Peace Matern & Child Hlth Hosp, Shanghai 200030, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai 200127, Peoples R China

[6] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Biomed Mat Engn, Dalian 116023, Peoples R China

[7] Inner Mongolia Univ, Key Lab Natl Educ, Minist Mammalian Reprod Biol & Biotechnol, Hohhot 010021, Peoples R China

[8] Univ Minnesota, Stem Cell Inst, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[9] Hepatoscience Inc, Palo Alto, CA 94303 USA

来源：

CELL STEM CELL | 2014年 / 14卷 / 03期

基金：

美国国家科学基金会;

关键词：

BIOARTIFICIAL LIVER; DRUG-METABOLISM; TRANSCRIPTION FACTORS; P53-DEFICIENT MICE; IN-VIVO; CELLS; CONVERSION; CHALLENGES; INDUCTION; FAILURE;

D O I：

10.1016/j.stem.2014.01.003

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

The generation of large numbers of functional human hepatocytes for cell-based approaches to liver disease is an important and unmet goal. Direct reprogramming of fibroblasts to hepatic lineages could offer a solution to this problem but so far has only been achieved with mouse cells. Here, we generated human induced hepatocytes (hiHeps) from fibroblasts by lentiviral expression of FOXA3, HNF1A, and HNF4A. hiHeps express hepatic gene programs, can be expanded in vitro, and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Upon transplantation into mice with concanavalin-A-induced acute liver failure and fatal metabolic liver disease due to fumarylacetoacetate dehydrolase (Fah) deficiency, hiHeps restore the liver function and prolong survival. Collectively, our results demonstrate successful lineage conversion of nonhepatic human cells into mature hepatocytes with potential for biomedical and pharmaceutical applications.

引用

页码：370 / 384

页数：15

共 47 条

[1] Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice [J].