Oncotarget

Research Papers:

Improvement of non-alcoholic steatohepatitis by hepatocyte-like cells generated from iPSCs with Oct4/Sox2/Klf4/Parp1

Yueh Chien, Chi-Shuan Huang, Hsin-Chi Lin, Kai-Hsi Lu, Ping-Hsing Tsai, Ying-Hsiu Lai, Kuan-Hsuan Chen, Shou-Dong Lee, Yi-Hsiang Huang and Chien-Ying Wang _

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Oncotarget. 2018; 9:18594-18606. https://doi.org/10.18632/oncotarget.23603

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Abstract

Yueh Chien1,9,*, Chi-Shuan Huang5,*, Hsin-Chi Lin3,4,*, Kai-Hsi Lu7, Ping-Hsing Tsai1,9, Ying-Hsiu Lai7, Kuan-Hsuan Chen2,10, Shou-Dong Lee6,8, Yi-Hsiang Huang8 and Chien-Ying Wang4,11

1Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC

2Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC

3Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC

4School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC

5Division of Colorectal Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC

6Division of Gastroenterology, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC

7Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC

8Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

9Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

10Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

11Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

*Equal co-first authors

Correspondence to:

Chien-Ying Wang, email: [email protected]

Keywords: non-alcoholic steatohepatitis; induced pluripotent stem cells

Received: September 04, 2017     Accepted: November 17, 2017     Epub: January 02, 2018     Published: April 06, 2018

ABSTRACT

The prevalence of nonalcoholic fatty liver disease (NAFLD) is usually increased with age. Non-alcoholic steatohepatitis (NASH), a serious form of NAFLD, may lead to cirrhosis and end-stage liver diseases. Induced pluripotent stem cells (iPSCs) hold promising potential in personalized medicine. Although obviation of c-Myc reduces tumorigenic risk, it also largely reduced the generation of iPSCs. Recently, Poly(ADP-ribose) polymerase 1 (Parp1) has been reported to enhance cell reprogramming. In this study, we demonstrated that forced expression of Oct4/Sox2/Klf4/Parp1 (OSKP) effectively promoted iPSC generation from senescent somatic cells from 18-month-old mouse. The iPSCs presented regular pluripotent properties, ability to form smaller teratoma with smaller size, and the potential for tridermal differentiation including hepatocyte-like cells (OSKP-iPSC-Heps). Resembled to fetal hepatocytes but not senescent hepatocytes, these OSKP-iPSC-Heps possessed antioxidant ability and were resistant to oxidative insult induced by H2O2 or exogenous fatty acid. Intrasplenic transplantation of OSKP-iPSC-Heps ameliorated the triglyceride over-accumulation and hepatitis, prevented the production of inflammatory cytokines and oxidative substances, and reduced apoptotic cells in methionine/choline-deficient diet (MCDD)-fed mice. In conclusion, we demonstrated that Parp-1 promoted iPSC generation from senescent cells, which can be used for the treatment of NASH after hepatic-specific differentiation. These findings indicated that patient-derived iPSC-Heps may offer an alternative option for treatment of NASH and NASH-associated end-stage liver diseases.


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