Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China; Institute of Translational Medicine, Zhejiang University, 310029 Hangzhou, China.
Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China.
J Mol Cell Cardiol. 2020 May;142:53-64. doi: 10.1016/j.yjmcc.2020.03.016. Epub 2020 Apr 3.
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.
糖尿病是一种严重的代谢性疾病，与多种心血管并发症有关。此外，心力衰竭患者中的糖尿病患病率高于对照人群。然而，2 型糖尿病（T2DM）中心肌细胞改变的作用尚未得到很好的描述，其潜在机制仍不清楚。在这项研究中，招募了两名被诊断为 T2DM 的患者，并使用非整合性 Sendai 病毒从尿液上皮细胞中生成了患者特异性诱导多能干细胞（iPSC）。来自五个健康受试者的 iPSC 系被用作对照。所有 iPSC 均使用基于单层的分化方案分化为心肌细胞（iPSC-CM）。T2DM iPSC-CM 表现出多种疾病表型，包括细胞肥大和脂质积累。此外，与对照 iPSC-CM 相比，T2DM iPSC-CM 对高糖/高脂刺激的敏感性更高，表现为细胞凋亡增加。RNA 测序分析显示 T2DM iPSC-CM 中存在差异转录组图谱和 TGFβ 信号通路的异常激活。我们进一步表明，抑制 TGFβ 可显著挽救 T2DM iPSC-CM 的肥大表型。总之，我们证明了 iPSC-CM 模型能够重现 T2DM 的细胞表型。我们的结果表明，因此，iPSC-CM 可以作为研究糖尿病心肌病分子机制和筛选治疗药物的合适模型。
