A Human 3D Cardiomyocyte Risk Model to Study the Cardiotoxic Influence of X-rays and Other Noxae in Adults

Abstract

The heart tissue is a potential target of various noxae contributing to the onset of cardiovascular diseases. However, underlying pathophysiological mechanisms are largely unknown. Human stem cell-derived models are promising, but a major concern is cell immaturity when estimating risks for adults. In this study, 3D aggregates of human embryonic stem cell-derived cardiomyocytes were cultivated for 300 days and characterized regarding degree of maturity, structure, and cell composition. Furthermore, effects of ionizing radiation (X-rays, 0.1–2 Gy) on matured aggregates were investigated, representing one of the noxae that are challenging to assess. Video-based functional analyses were correlated to changes in the proteome after irradiation. Cardiomyocytes reached maximum maturity after 100 days in cultivation, judged by α-actinin lengths, and displayed typical multinucleation and branching. At this time, aggregates contained all major cardiac cell types, proven by the patch-clamp technique. Matured and X-ray-irradiated aggregates revealed a subtle increase in beat rates and a more arrhythmic sequence of cellular depolarisation and repolarisation compared to non-irradiated sham controls. The proteome analysis provides first insights into signaling mechanisms contributing to cardiotoxicity. Here, we propose an in vitro model suitable to screen various noxae to target adult cardiotoxicity by preserving all the benefits of a 3D tissue culture.

Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

“…Here, the improved Ca 2+ current density, increased CaT amplitude, decreased CaT decay tau, and prolonged APD 90 observed in PC compared to RM may be due to enhanced ATP transport between SR and the sarcomere in PC, although further studies are needed to prove these links. Last, we also observed significantly increased multinucleation rates in iPSC-aCMs in PC (25 to 50%) compared to RM (10 to 20%), which may reflect the induction of cell cycle withdrawal ( 25 , 49 , 50 ). iPSC-aCMs in PC up-regulated the gene expression of cyclin-dependent kinase inhibitors, CDKN2A and CDKN2B , important for cell cycle withdrawal ( 49 ).…”

“…iPSC-aCMs in PC up-regulated the gene expression of cyclin-dependent kinase inhibitors, CDKN2A and CDKN2B , important for cell cycle withdrawal ( 49 ). Previous studies have shown that long-term culture (>100 days) was required to achieve iPSC-aCM bi/multinucleation ( 25 , 50 ), whereas iPSC-aCMs in PC achieved these outcomes in ~45 days, suggesting an accelerated maturation timeline useful for more timely execution of compound screening and disease modeling.…”

Rotational Activity around an Obstacle in 2D Cardiac Tissue in Presence of Cellular Heterogeneity

“…However, the applications of mathematical methods in cardiac research are much more wide-ranging, for example, for the analysis of population studies [41]. Moreover, currently in vitro cardiac models from stem cells are of great interest [42,43]. Such a system can also be studied using corresponding mathematical models [44].…”