最近，美国桑福德-伯纳姆医学研究所和约翰·霍普金斯大学的研究人员合作，用一种遗传性心脏病患者的皮肤细胞培育出心肌细胞，并在培养皿中诱导出心脏病模型，再现了该病发作时的主要特征。研究人员指出，这一成果有助于人们更好地研究该病，测试新的治疗方法。相关论文发表在1月27日的《自然》杂志上。
这一遗传性心脏病叫心律失常性右室发育不良/右室心肌病（ARVD/C）。大多数该病患者在20岁之前没有征兆，因此很难研究其进展情况和相应疗法。论文高级作者、桑福德-伯纳姆医学研究所副教授惠生文森特·陈说：“要证明培养皿中的疾病模型和成人患者疾病之间具有临床相关性是非常困难的。ARVD/C症状通常到青年期才会显出来，而我们用的干细胞在性质上属于胚胎。但我们的研究有一项关键突破，诱导胚胎细胞拥有了成人心肌的新陈代谢。”
研究人员先从ARVD/C患者身上采集皮肤细胞，这些细胞含有与该病相关的遗传变异；然后加入某些分子，让成人皮肤细胞逆转回到类似胚胎状态，也就是诱导多能干细胞（iPSCs）状态；再进一步诱导iPSCs，使其能无限供给患者特有的心肌细胞。这些心肌细胞拥有大部分的胚胎性质，但同时又携带了患者最初的遗传变异。
培养皿中处于胚胎阶段的ARVD/C心肌细胞在一年内都未显出任何疾病的迹象。他们用了一些混合物，诱导心肌细胞的新陈代谢由胚胎方式转换成成人方式。新陈代谢成熟是诱导胚胎心肌细胞产生成人ARVD/C信号的关键，因为人类胎儿心肌细胞是以葡萄糖为主要能源，而成人心肌细胞是用脂肪。他们还在诱变后的心肌细胞中发现了ARVD/C心脏的特征，一种叫做PPAR的蛋白过度活跃。
研究人员指出，新模型在培养皿中再现了这种疾病，为治疗该病提供了新的潜在药物标靶。约翰·霍普金斯大学医学院遗传心脏病中心副教授与医学主管丹尼尔·加杰说：“目前，世界上还没有预防ARVD/C发展的方法，有了这一新模型，我们希望能对这种威胁生命的疾病，开发出更好的治疗方法。”
Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs
Changsung Kim, Johnson Wong, Jianyan Wen, Shirong Wang, Cheng Wang, Sean Spiering, Natalia G. Kan, Sonia Forcales, Pier Lorenzo Puri, Teresa C. Leone, Joseph E. Marine, Hugh Calkins, Daniel P. Kelly, Daniel P. Judge & Huei-Sheng Vincent Chen
Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging owing to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle, which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2, encoding plakophilin-2 . The median age at presentation of ARVD/C is 26 years8. We used previously published methods1, 10 to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity13 in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPAR-γ) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-γ pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in vitro model within 2 months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also had calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.
文献链接：Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs
