Final Report Summary - CARDIONECT (Cardiac Connective Tissue: Beat-by-Beat Relevance for Heart Function in Health and Disease)
Like any other complex organ, the heart consists of different interacting cell populations. Fundamental and applied heart research so far has focussed mainly on muscle cells, whose coordinated electrical activation gives rise to well-synchronised mechanical contraction. This, in turn, underlies the heart-beat. Interestingly, while myocytes occupy the largest part of cardiac tissue volume, other (smaller) cells are significantly more numerous. Among these ‘majority cell populations’, connective tissue cells called fibroblasts, and immune cells called macrophages, are of particular interest. Fibroblasts are instrumental in making the deformable extra-cellular matrix ‘skeleton’ of the heart, and macrophages act as tissue-resident protectors that, for example, clean-up debris shed from other cells including muscle cells. Beyond these ‘canonical functions’, both cell types fulfil a number of biochemical signalling functions that are a target of ongoing research. What is less well known is that they may also serve as *biophysical_signalling* hubs in the heart, with important mechanical and electrical roles for normal and disturbed heart function. These include electrical insulation of regions of heart muscle that benefit from sequential activation and, counter-intuitively, the electrical connections with/ between muscle cells. Within this project, we have confirmed that cardiomyocytes can drive the electrical activity in fibroblasts in native myocardium, while macrophages can electrically signal to alter cardiomyocyte activity in the heart. The molecular substrates underlying these hetero-cellular interactions go beyond classic connexin-based links, and include tunneling nanotubes. Exploration of their relevance in development, homeostasis, disease and therapy constitutes a novel research area that has emerged during the tenure of this AdG.