Chemical cocktails enable hepatic reprogramming of human urine-derived cells with a single transcription factor

Wei Tang; Ren Guo; Shi-Jun Shen; Yang Zheng; Yu-Ting Lu; Meng-Meng Jiang; Xue Cui; Ci-Zhong Jiang; Xin Xie

doi:10.1038/s41401-018-0170-z

Chemical cocktails enable hepatic reprogramming of human urine-derived cells with a single transcription factor

Acta Pharmacol Sin. 2019 May;40(5):620-629. doi: 10.1038/s41401-018-0170-z. Epub 2018 Oct 12.

Authors

Wei Tang^{1

2}, Ren Guo^{2

3}, Shi-Jun Shen¹, Yang Zheng^{2

3

4}, Yu-Ting Lu^{3

4

5}, Meng-Meng Jiang^{2

3

4}, Xue Cui^{1

2}, Ci-Zhong Jiang¹, Xin Xie^{6

7

8

9}

Affiliations

¹ Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
² CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, 201203, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁶ Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. xxie@simm.ac.cn.
⁷ CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xxie@simm.ac.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xxie@simm.ac.cn.
⁹ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. xxie@simm.ac.cn.

Abstract

Human liver or hepatocyte transplantation is limited by a severe shortage of donor organs. Direct reprogramming of other adult cells into hepatic cells may offer a solution to this problem. In a previous study, we have generated hepatocyte-like cells from mouse fibroblasts using only one transcription factor (TF) plus a chemical cocktail. Here, we show that human urine-derived epithelial-like cells (hUCs) can also be transdifferentiated into human hepatocyte-like cells (hiHeps) using one TF (Foxa3, Hnf1α, or Hnf4α) plus the same chemical cocktail CRVPTD (C, CHIR99021; R, RepSox; V, VPA; P, Parnate; T, TTNPB; and D, Dznep). These hiHeps express multiple hepatocyte-specific genes and display functions characteristic of mature hepatocytes. With the introduction of the large T antigen, these hiHeps can be expanded in vitro and can restore liver function in mice with concanavalin-A-induced acute liver failure. Our study provides a strategy to generate functional hepatocyte-like cells from hUCs by using a single TF plus a chemical cocktail.

Keywords: chemical cocktail; hepatic transdifferentiation; human urine-derived cells; regenerative medicine; reprogramming.

MeSH terms

Animals
Cellular Reprogramming Techniques / methods*
Cellular Reprogramming*
Concanavalin A
Epithelial Cells / cytology*
Epithelial Cells / metabolism
HEK293 Cells
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 3-gamma / genetics
Hepatocyte Nuclear Factor 4 / genetics
Hepatocytes / cytology*
Hepatocytes / transplantation
Humans
Liver Failure, Acute / chemically induced
Liver Failure, Acute / therapy*
Male
Mice
Transfection
Urine / cytology*
Young Adult

Substances

FOXA3 protein, human
HNF1A protein, human
HNF4A protein, human
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 4
Concanavalin A
Hepatocyte Nuclear Factor 3-gamma