J Mol Cell Cardiol. 2020 Apr 3. pii: S0022-2828(20)30081-X. doi: 10.1016/j.yjmcc.2020.03.016. [Epub ahead of print]

Human induced pluripotent stem cell-derived cardiomyocytes reveal abnormal TGFβ signaling in type 2 diabetes mellitus.

Tang L¹, Wang H¹, Dai B², Wang X¹, Zhou D¹, Shen J¹, Guo F¹, Wang J¹, Zhou J¹, Wang H³, Wu Q⁴, Yao H⁵, Gong T⁶, Su J¹, Meng ZX⁷, Niu T⁸, Zhang L⁹, Liang P¹⁰.

Abstract

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.