Diabetes mellitus is a serious metabolic condition associated with a multitude of cardiovascular complications. Moreover, the prevalence of diabetes in heart failure populations is higher than that in control populations. However, the role of cardiomyocyte alterations in type 2 diabetes mellitus (T2DM) has not been well characterized and the underlying mechanisms remain elusive. In this study, two patients who were diagnosed as T2DM were recruited and patient-specific induced pluripotent stem cells (iPSCs) were generated from urine epithelial cells using nonintegrated Sendai virus. The iPSC lines derived from five healthy subjects were used as controls. All iPSCs were differentiated into cardiomyocytes (iPSC-CMs) using the monolayer-based differentiation protocol. T2DM iPSC-CMs exhibited various disease phenotypes, including cellular hypertrophy and lipid accumulation. Moreover, T2DM iPSC-CMs exhibited higher susceptibility to high-glucose/high-lipid challenge than control iPSC-CMs, manifesting an increase in apoptosis. RNA-Sequencing analysis revealed a differential transcriptome profile and abnormal activation of TGFβ signaling pathway in T2DM iPSC-CMs. We went on to show that inhibition of TGFβ significantly rescued the hypertrophic phenotype in T2DM iPSC-CMs. In conclusion, we demonstrate that the iPSC-CM model is able to recapitulate cellular phenotype of T2DM. Our results indicate that iPSC-CMs can therefore serve as a suitable model for investigating molecular mechanisms underlying diabetic cardiomyopathies and for screening therapeutic drugs.

中文翻译：

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人类诱导的多能干细胞衍生的心肌细胞在2型糖尿病中显示出异常的TGFβ信号传导。

糖尿病是一种严重的代谢疾病，伴有多种心血管并发症。此外，心力衰竭人群的糖尿病患病率高于正常人群。然而，心肌细胞改变在2型糖尿病（T2DM）中的作用尚未得到很好的表征，其潜在机制仍然难以捉摸。在这项研究中，招募了两名被诊断为T2DM的患者，并使用非整合型仙台病毒从尿液上皮细胞中生成了患者特异性诱导的多能干细胞（iPSC）。来自五个健康受试者的iPSC系用作对照。使用基于单层的分化方案将所有iPSC分化为心肌细胞（iPSC-CM）。T2DM iPSC-CM表现出多种疾病表型，包括细胞肥大和脂质堆积。此外，T2DM iPSC-CM与对照iPSC-CM相比，对高葡萄糖/高脂质攻击表现出更高的敏感性，表明细胞凋亡增加。RNA测序分析显示，T2DM iPSC-CM中转录组谱差异和TGFβ信号通路异常激活。我们继续表明，TGFβ的抑制作用显着拯救了T2DM iPSC-CM中的肥大表型。总之，我们证明了iPSC-CM模型能够概括T2DM的细胞表型。我们的结果表明，iPSC-CMs因此可以用作研究糖尿病性心肌病潜在分子机制和筛选治疗药物的合适模型。T2DM iPSC-CM与对照iPSC-CM相比，对高葡萄糖/高脂质攻击的敏感性更高，表现出细胞凋亡的增加。RNA测序分析显示，T2DM iPSC-CM中转录组谱差异和TGFβ信号通路异常激活。我们继续表明，TGFβ的抑制作用显着拯救了T2DM iPSC-CM中的肥大表型。总之，我们证明了iPSC-CM模型能够概括T2DM的细胞表型。我们的结果表明，iPSC-CMs因此可以用作研究糖尿病性心肌病潜在分子机制和筛选治疗药物的合适模型。T2DM iPSC-CM与对照iPSC-CM相比，对高葡萄糖/高脂质攻击的敏感性更高，表现出细胞凋亡的增加。RNA测序分析显示，T2DM iPSC-CM中转录组谱差异和TGFβ信号通路异常激活。我们继续表明，TGFβ的抑制作用显着拯救了T2DM iPSC-CM中的肥大表型。总之，我们证明了iPSC-CM模型能够概括T2DM的细胞表型。我们的结果表明，iPSC-CMs因此可以用作研究糖尿病性心肌病潜在分子机制和筛选治疗药物的合适模型。RNA测序分析显示，T2DM iPSC-CM中转录组谱差异和TGFβ信号通路异常激活。我们继续表明，TGFβ的抑制作用显着拯救了T2DM iPSC-CM中的肥大表型。总之，我们证明了iPSC-CM模型能够概括T2DM的细胞表型。我们的结果表明，iPSC-CMs因此可以用作研究糖尿病性心肌病潜在分子机制和筛选治疗药物的合适模型。RNA测序分析显示，T2DM iPSC-CM中转录组谱差异和TGFβ信号通路异常激活。我们继续表明，TGFβ的抑制作用显着拯救了T2DM iPSC-CM中的肥大表型。总之，我们证明了iPSC-CM模型能够概括T2DM的细胞表型。我们的结果表明，iPSC-CMs因此可以用作研究糖尿病性心肌病潜在分子机制和筛选治疗药物的合适模型。