Chou Shih-Jie, Yu Wen-Chung, Chang Yuh-Lih, Chen Wen-Yeh, Chang Wei-Chao, Chien Yueh, Yen Jiin-Cherng, Liu Yung-Yang, Chen Shih-Jen, Wang Chien-Ying, Chen Yu-Han, Niu Dau-Ming, Lin Shing-Jong, Chen Jaw-Wen, Chiou Shih-Hwa, Leu Hsin-Bang
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Int J Cardiol. 2017 Apr 1;232:255-263. doi: 10.1016/j.ijcard.2017.01.009. Epub 2017 Jan 5.
Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood.
We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease.
Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs.
The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs.
This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease.
法布里病（FD）是一种溶酶体贮积病，其中糖鞘脂（GB3）在人体器官中蓄积，导致特发性肥厚型心肌病和靶器官损伤。其病理生理学仍知之甚少。
我们旨在从患有心肌病的FD患者中生成患者特异性诱导多能干细胞（iPSC），以确定该模型是否能够重现疾病表型的关键特征，并研究法布里病中的能量代谢。
将一名诊断为法布里病、GLA基因（IVS4+919G>A）突变的30岁中国男性的外周血单个核细胞重编程为iPSC，并分化为iPSC-CM，然后对iPSC-CM中的能量代谢进行分析。
FD-iPSC-CM重现了FD表型的多个方面，包括GLA活性降低、细胞肥大、GB3蓄积和收缩功能受损。观察到能量代谢降低且能量利用转向糖酵解，但FD-iPSC-CM中的能量代谢降低并未因酶替代疗法（ERT）而改变。
该模型为研究FD潜在疾病机制和开发新治疗策略提供了一个有前景的体外模型。这种增强能量网络和利用效率的潜在疗法值得进一步研究，以确定该疾病的新疗法。
