Abstract
Studies over the past two decades have shown heart regeneration in zebrafish to be a dynamic process, choreographed by multiple cell types. In particular, recent work has identified revascularization of the wound to be a sentinel event during heart regeneration. The cardiac endothelium has emerged as a key orchestrator of heart regeneration, influencing cardiomyocyte hyperplasia and tissue morphogenesis. Here, we review how the coronary vasculature regenerates after injury, how signaling pathways link the cardiac endothelium to heart regeneration, and how understanding these signaling dynamics can lead to targeted therapies for heart regeneration.
Highlights
250,000–500,000 Americans suffer from advanced heart failure refractory to guideline-directed medical therapy [1]
We provide a focused overview of how the coronary vasculature regenerates after injury and the signaling pathways that link the cardiac endothelium to heart regeneration
For the purpose of this review, we consider the endocardium and the coronary vascular endothelium to make up the cardiac endothelium, as these endothelial populations have a similar ontogeny and highly overlapping marker profiles
Summary
Axolotls and zebrafish are able to replace lost cardiac tissue through tissue regeneration [3,4,5]. Non-regenerative organisms have a limited capacity for cardiomyocyte hyperplasia after injury [10]. Based on these observations, stimulating cardiomyocyte proliferation has emerged as a focal point for methods to enhance the regenerative capacity of the mammalian heart [11,12]. Interference with revascularization responses, epicardial responses, or fibroblast responses limits the extent of cardiomyocyte proliferation and heart regeneration [18,20]. Specialized regulatory T-cells that infiltrate the wound express tissue-specific mitogens in response to injury [22]. Macrophages are likely to have pro-regenerative paracrine effects [23] Together, this wealth of data highlights the concerted and complex contributions of multiple tissues for natural heart regeneration
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