Accumulation of Toxic Advanced Glycation End-Products Induces Cytotoxicity and Inflammation in Hepatocyte-Like Cells Differentiated from Human Induced Pluripotent Stem Cells
Accumulation of Toxic Advanced Glycation End-Products Induces Cytotoxicity and Inflammation in Hepatocyte-Like Cells Differentiated from Human Induced Pluripotent Stem Cells
复制标题
DOI：
10.1248/bpb.b21-00520
复制
发表时间：
2021-10-01
影响因子：
2
通讯作者：
Matsunaga, Tamihide
中科院分区：
文献类型：
--
作者：
Kikuchi, Chigusa;Sakasai-Sakai, Akiko;Matsunaga, Tamihide
非酒精性脂肪性肝炎（NASH）是最常见的慢性肝病非酒精性脂肪性肝病的侵袭性形式，其特征在于肝脏中的炎症和损伤。虽然肝细胞损伤和细胞死亡已被确定为NASH的主要病理特征，但其发病机制尚未详细阐明。永生化细胞系和原代培养细胞已被用作NASH的体外模型。然而，这些细胞有几个缺点，如永生化的特化特征或有限的生长潜力。为了克服这些困难并开发一种分析NASH病理学的策略，我们采用从人诱导多能干细胞（hiPSC-HLC）分化的肝细胞样细胞作为NASH的体外模型，以阐明甘油三酸酯衍生的晚期糖基化终产物（AGEs）（也称为毒性AGEs（TAGE））的细胞内作用。hiPSC-HLCs的活力随着TAGE在细胞中的积累而降低，这与先前对人肝细胞癌细胞和人原代培养肝细胞的发现一致。此外，TAGE蓄积上调hiPSC-HLCs中炎症相关基因（白介素6、白介素8和单核细胞趋化蛋白-1）的表达。这些结果表明TAGE的积累诱导了hiPSC-HLC细胞毒性和炎症，这是NASH病理学的特征。因此，我们建议使用hiPSC-HLC作为NASH病理学分析的重要策略。
Nonalcoholic steatohepatitis (NASH), the aggressive form of the most common chronic liver disease nonalcoholic fatty liver disease, is characterized by inflammation and damage in the liver. Although hepatocyte injury and cell death have been identified as cardinal pathological features of NASH, its pathogenesis has not yet been elucidated in detail. Immortalized cell lines and primary cultured cells have been used as in vitro models of NASH. However, these cells have several disadvantages, such as specialized characteristics by immortalization or limited growth potential. To overcome these difficulties and develop a strategy to analyze the pathology of NASH, we employed hepatocyte-like cells differentiated from human induced pluripotent stem cells (hiPSC-HLCs) as an in vitro model of NASH to clarify the intracellular effects of glyceraldehyde-derived advanced glycation end-products (AGEs), also named toxic AGEs (TAGE). The viability of hiPSC-HLCs decreased with the accumulation of TAGE in the cells, which was consistent with previous findings on human hepatocellular carcinoma cells and human primary cultured hepatocytes. In addition, the TAGE accumulation up-regulated the expression of inflammation-related genes (interleukin 6, interleukin 8, and monocyte chemoattractant protein-1) in hiPSC-HLCs. These results indicated that the accumulation of TAGE induced hiPSC-HLC cytotoxicity and inflammation, which are features of the pathology of NASH. Therefore, we suggest the use of hiPSC-HLCs as an important strategy for analyses of the pathology of NASH.