Maturation-Based Model of Arrhythmogenic Right Ventricular Dysplasia Using Patient-Specific Induced Pluripotent Stem Cells
Maturation-Based Model of Arrhythmogenic Right Ventricular Dysplasia Using Patient-Specific Induced Pluripotent Stem Cells
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DOI：
10.1253/circj.cj-15-0363
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发表时间：
2015-07-01
影响因子：
3.3
通讯作者：
Chen, Huei-Sheng Vincent
中科院分区：
文献类型：
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作者：
Wen, Jian-Yan;Wei, Chuan-Yu;Chen, Huei-Sheng Vincent
将体细胞细胞重编程为患者特异性诱导多能干细胞（iPSC）使得能够在体外建模人类心脏疾病用于致病性和治疗性研究。然而，使用iPSC衍生的心肌细胞（iPSC-CM）来模拟成人发作的心脏病仍然具有挑战性，因为关于相对不成熟的iPSC-CM完全再现成人疾病表型的能力的不确定性。致心律失常性右心室发育不良（ARVD）是一种遗传性心肌病，其特征是病理性纤维脂肪浸润和心肌细胞（CM）损失，主要发生在右心室（RV），导致心力衰竭和致命性心律失常。超过50%的受影响个体具有桥粒基因突变，最常见于编码斑嗜蛋白-2的PKP 2。使用Yamanaka的多能因子，我们从具有PKP 2突变的ARVD患者产生iPSC系。我们首先开发了一种诱导iPSC-CM代谢成熟的方法，并表明从胚胎/糖酵解状态诱导成人样代谢能量学对于使用患者特异性iPSC模拟成人发作的心脏病至关重要。此外，我们发现，共激活正常过氧化物酶体增殖物激活受体（PPAR）-α和异常的过氧化物酶体增殖物激活受体。在ARVD iPSC-CM中的这些通路导致CM脂肪生成过度、CM凋亡、Na+通道下调和细胞内钙处理缺陷，重现了ARVD的病理特征。使用该模型，我们揭示了新的致病见解，即成人样代谢环境中的代谢紊乱是ARVD病理的基础，使我们能够提出新的疾病修饰治疗策略。
Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in-vitro modeling of human cardiac disorders for pathogenic and therapeutic investigations. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging because of the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by pathological fibrofatty infiltration and cardiomyocyte (CM) loss predominantly in the right ventricle (RV), leading to heart failure and lethal arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2 encoding plakophilin-2. Using Yamanaka's pluripotent factors, we generated iPSC lines from ARVD patients with PKP2 mutations. We first developed a method to induce metabolic maturation of iPSC-CMs and showed that induction of adult-like metabolic energetics from an embryonic/glycolytic state is essential to model an adult-onset cardiac disease using patient-specific iPSCs. Furthermore, we showed that coactivation of normal peroxisome proliferator-activated receptor (PPAR)-alpha and abnormal PPAR. pathways in ARVD iPSC-CMs resulted in exaggerated CM lipogenesis, CM apoptosis, Na+ channel downregulation and defective intracellular calcium handling, recapitulating the pathological signatures of ARVD. Using this model, we revealed novel pathogenic insights that metabolic derangement in an adult-like metabolic milieu underlies ARVD pathologies, enabling us to propose novel disease-modifying therapeutic strategies.