Tissue and cellular adaptability and plasticity determine cardiac phenotypes but are difficult to elicit in in vitro models. In this talk, I will present two models where plasticity is accounted for: the living myocardial slices, subjected to electromechanical stimulation (Watson et al., 2017, 2019; Pitoulis et al., 2021), and the micro vascularised engineered myocardium, composed of human iPSC-derived cardiomyocytes and human microvascular endothelial cells (King et al., 2022).

The living myocardial slices are the gold standard to study heterocellular interactions in vitro because they are derived from the whole, native myocardium, containing all the cellular and extracellular components. They can be obtained from hearts of many species, including human failing and non-failing hearts, can be cultured for several days/weeks and respond promptly to environmental changes. We have developed bioreactors to maintain and manipulate the electromechanical status of the slices in physiology and disease. We can specifically manipulate preload and/or afterload in long term cultures and have described methods to study individual cell types within the slices, or after isolation. We are thus able to simulate disease in slices, e.g. mechanical overload (Nunez-Toldra et al., 2022), ischemia-reperfusion injury and focal injury. We can genetically modify living myocardial slices using viral vectors, opening novel and more relevant avenues for investigating cardiac disease.

The micro vascularised, IPSC-derived myocardium allows studying specifically into the cross talk between endothelial cells and cardiomyocytes when both contraction and vascular flow are present. In this model, contractility and flow in the engineered micro vessels can be manipulated and the consequences on the heterocellular interactions studied. This model is a step forward in physiological cardiac tissue engineering and represents a relevant tool to understanding cell-cell interaction in the heart.