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

// Yueh Chien 1, 9, * , Chi-Shuan Huang 5, * , Hsin-Chi Lin 3, 4, * , Kai-Hsi Lu 7 , Ping-Hsing Tsai 1, 9 , Ying-Hsiu Lai 7 , Kuan-Hsuan Chen 2, 10 , Shou-Dong Lee 6, 8 , Yi-Hsiang Huang 8 and Chien-Ying Wang 4, 11 1 Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC 2 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC 3 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC 4 School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC 5 Division of Colorectal Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC 6 Division of Gastroenterology, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC 7 Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC 8 Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC 9 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC 10 Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan, ROC 11 Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC * Equal co-first authors Correspondence to: Chien-Ying Wang, email: wangcy@vghtpe.gov.tw 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 H 2 O 2 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.