Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells
Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells
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DOI：
10.1016/j.celrep.2014.09.055
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发表时间：
2014-11-06
期刊：
影响因子：
8.8
通讯作者：
Iacone, Roberto
中科院分区：
文献类型：
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作者：
Drawnel, Faye M.;Boccardo, Stefano;Iacone, Roberto
糖尿病性心肌病是2型糖尿病的并发症，已知与生活方式和遗传有关。我们开发了环境和遗传驱动的体外模型的条件，使用人类诱导多能干细胞衍生的心肌细胞。首先，我们模拟糖尿病临床化学诱导糖尿病心肌病的表型替代，观察结构和功能紊乱。接下来，我们考虑遗传效应，从两个糖尿病患者与变量疾病进展的心肌细胞。心肌病表型在患者特异性细胞中基本重现，严重程度取决于其原始临床状态。这些模型被整合到筛选平台的连续水平中，以鉴定在糖尿病应激期间在体外保持心肌细胞表型的药物。在这项工作中，我们提出了一种复杂代谢条件的患者特异性诱导多能干细胞（iPSC）模型，显示了这种技术在发现和测试具有不断增加的临床意义的疾病的治疗策略方面的能力。
Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.