Yasuda Katsutaro, Kotaka Maki, Toyohara Takafumi, Sueta Shin-Ichi, Katakai Yuko, Ageyama Naohide, Uemoto Shinji, Osafune Kenji
Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; Department of Hepatobiliary Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Biochem Biophys Res Commun. 2020 Jun 4;526(3):661-669. doi: 10.1016/j.bbrc.2020.03.148. Epub 2020 Apr 2.
Orthotopic liver transplantation (OLT) is the only curative treatment for refractory chronic liver failure in liver cirrhosis. However, the supply of donated livers does not meet the demand for OLT due to donor organ shortage. Cell therapy using hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-HLCs) is expected to mitigate the severity of liver failure, postpone OLT and ameliorate the insufficient liver supply. For the successful clinical translation of hiPSC-based cell therapy against liver cirrhosis, realistic animal models are required. In this study, we created a nonhuman primate (NHP) liver fibrosis model by repeated administrations of thioacetamide (TAA) and evaluated the short-term engraftment of hiPSC-HLCs in the fibrotic liver. The NHP liver fibrosis model reproduced well the pathophysiology of human liver cirrhosis including portal hypertension. Under immunosuppressive treatment, we transplanted ALBUMIN-GFP reporter hiPSC-HLC aggregates into the fibrotic livers of the NHP model via the portal vein. Fourteen days after the transplantation, GFP-expressing hiPSC-HLC clusters were detected in the portal areas of the fibrotic livers. These results will facilitate preclinical studies using the NHP liver fibrosis model and help establish iPSC-based cell therapies against liver cirrhosis.
原位肝移植（OLT）是肝硬化难治性慢性肝衰竭的唯一治愈性治疗方法。然而，由于供体器官短缺，捐赠肝脏的供应无法满足OLT的需求。使用源自人诱导多能干细胞的肝样细胞（hiPSC-HLCs）进行细胞治疗有望减轻肝衰竭的严重程度、推迟OLT并改善肝脏供应不足的问题。为了使基于hiPSC的细胞治疗肝硬化成功实现临床转化，需要现实可行的动物模型。在本研究中，我们通过反复给予硫代乙酰胺（TAA）建立了非人类灵长类动物（NHP）肝纤维化模型，并评估了hiPSC-HLCs在纤维化肝脏中的短期植入情况。NHP肝纤维化模型很好地再现了包括门静脉高压在内的人类肝硬化的病理生理学。在免疫抑制治疗下，我们通过门静脉将白蛋白-GFP报告基因hiPSC-HLC聚集体移植到NHP模型的纤维化肝脏中。移植后14天，在纤维化肝脏的门静脉区域检测到表达GFP的hiPSC-HLC簇。这些结果将促进使用NHP肝纤维化模型的临床前研究，并有助于建立基于iPSC的肝硬化细胞治疗方法。
