Functional and molecular effects of TNF-α on human iPSC-derived cardiomyocytes

Abstract

Proinflammatory molecule tumor necrosis factor alpha (TNF-α) is predominantly elevated in cytokine storm as well as worsening cardiac function. Here we model the molecular and functional effects of TNF-α in cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC). We found that treatment of hiPSC-CMs with TNF-α increased reactive oxygen species (ROS) and caspase 3/7 activity and caused cell death and apoptosis. TNF-α treatment also resulted in dysregulation of cardiomyocyte function with respect to the increased abnormal calcium handling, calcium wave propagation between cells and excitation–contraction coupling. We also uncovered significant changes in gene expression and protein localization caused by TNF-α treatment. Notably, TNF-α treatment altered the expression of ion channels, dysregulated cadherins, and affected the localization of gap-junction protein connexin-43. In addition, TNF-α treatment up-regulated IL-32 (a human specific cytokine, not present in rodents and an inducer of TNF-α) and IL-34 and down-regulated glutamate receptors and cardiomyocyte contractile proteins. These findings provide insights into the molecular and functional consequences from the exposure of human cardiomyocytes to TNF-α. Our study provides a model to incorporate inflammatory factors into hiPSC-CM-based studies to evaluate mechanistic aspects of heart disease.

Space microgravity improves proliferation of human iPSC-derived cardiomyocytes

“…ISS mG samples had more cells with normal Ca 2+ transients compared with ISS 1G samples (93% in ISS mG cells versus 78% in ISS 1G cells) (Figure 5B). The proportion of the cells with abnormal Ca 2+ transients and the types of abnormal Ca 2+ transients in ISS 1G cultures were comparable with typical hiPSC-CM cultures in ground-based studies (Forghani et al, 2021;Lan et al, 2013;Liu et al, 2020a;Saraf et al, 2021). Most of these abnormal cells had minor abnormality with inconsistent beating period (type B) and a few cells had transients with a single notch of additional Ca 2+ spike (diastolic Ca 2+ signal) before the following Ca 2+ transient had initiated (type A) (Figures 5A and 5B).…”

MicroRNA-181b Serves as a Circulating Biomarker and Regulates Inflammation in Heart Failure

“…The components of inflammatory mediators include TNF-α and the IL-1 family and the IL-6 family, which are the focus of the current research [3]. Previous studies have confirmed that these proinflammatory cytokines can be expressed by all nucleated cell types residing in the myocardium, including cardiomyocyte [31]. The overexpression of cytokine cascades contributes to HF progression [3].…”

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

“…Specifically influencing the mechanical activity of cardiac cells, such effects include direct posttranslational modifications of proteins of the excitation-contraction coupling machinery. Prolonged imbalance in the redox state of cardiomyocytes leads to instable Ca 2+ handling and arrhythmogenic modifications [ 42 , 43 ]. Moreover, disorders of Ca 2+ handling and Ca 2+ overload influence Cx43 channel function.…”