Oncotarget

Research Papers:

Generation of functional hepatocytes from human spermatogonial stem cells

Zheng Chen, Min Sun, Qingqing Yuan, Minghui Niu, Chencheng Yao, Jingmei Hou, Hong Wang, Liping Wen, Yun Liu, Zheng Li and Zuping He _

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Oncotarget. 2016; 7:8879-8895. https://doi.org/10.18632/oncotarget.7092

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Abstract

Zheng Chen1, Min Sun1, Qingqing Yuan1, Minghui Niu1, Chencheng Yao1, Jingmei Hou1, Hong Wang1, Liping Wen1, Yun Liu1, Zheng Li2, Zuping He1,2,3,4

1State Key Laboratory of Oncogenes and Related Genes, Renji- Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China

2Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Andrology, Shanghai 200001, China

3Shanghai Key Laboratory of Assisted Reproduction and Reproductive Genetics, Shanghai 200127, China

4Shanghai Key Laboratory of Reproductive Medicine, Shanghai 200025, China

Correspondence to:

Zuping He, e-mail: zupinghe@sjtu.edu.cn

Keywords: human spermatogonial stem cells, transdifferentiation, hepatic stem cells, mature and functional hepatocytes

Received: August 18, 2015     Accepted: January 17, 2016     Published: January 31, 2016

ABSTRACT

To generate functional human hepatocytes from stem cells and/or extra-hepatic tissues could provide an important source of cells for treating liver diseases. Spermatogonial stem cells (SSCs) have an unlimited plasticity since they can dedifferentiate and transdifferentiate to other cell lineages. However, generation of mature and functional hepatocytes from human SSCs has not yet been achieved. Here we have for the first time reported direct transdifferentiation of human SSCs to mature and functional hepatocytes by three-step induction using the defined condition medium. Human SSCs were first transdifferentiated to hepatic stem cells, as evidenced by their morphology and biopotential nature of co-expressing hepatocyte and cholangiocyte markers but not hallmarks for embryonic stem cells. Hepatic stem cells were further induced to differentiate into mature hepatocytes identified by their morphological traits and strong expression of CK8, CK18, ALB, AAT, TF, TAT, and cytochrome enzymes rather than CK7 or CK19. Significantly, mature hepatocytes derived from human SSCs assumed functional attributes of human hepatocytes, because they could produce albumin, remove ammonia, and uptake and release indocyanine green. Moreover, expression of β-CATENIN, HNF4A, FOXA1 and GATA4 was upregulated during the transdifferentiation of human SSCs to mature hepatocytes. Collectively, human SSCs could directly transdifferentiate to mature and functional hepatocytes. This study could offer an invaluable source of human hepatocytes for curing liver disorders and drug toxicology screening and provide novel insights into mechanisms underlying human liver regeneration.


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