Approaches to augment vascularisation and regeneration of the adult heart via the reactivated epicardium

Abstract

Survival rates following myocardial infarction have increased in recent years but current treatments for post-infarction recovery are inadequate and cannot induce regeneration of damaged hearts. Regenerative medicine could provide disease-reversing treatments by harnessing modern concepts in cell and developmental biology. A recently-established paradigm in regenerative medicine is that regeneration of a tissue can be achieved by reactivation of the coordinated developmental processes that originally formed the tissue. In the heart, the epicardium has emerged as an important regulator of cardiac development and reactivation of epicardial developmental processes may provide a means to enable cardiac regeneration. Indeed, in adult mouse hearts, treatment with thymosin β4 and other drug-like molecules reactivates the epicardium and improves outcomes after myocardial infarction by inducing regenerative paracrine signalling, neovascularisation and de novo cardiomyocyte production. However, there are considerable limitations to current methods of epicardial reactivation that prevent direct translation into clinical practice. Here, we describe the rationale for targeting the epicardium and the successes and limitations of this approach. We consider how several recent advances in epicardial biology could be used to overcome these limitations. These advances include insight into epicardial signalling and heterogeneity, epicardial modulation of inflammation and epicardial remodelling of extracellular matrix.

Proepicardium: Current Understanding of its Structure, Induction, and Fate

“…Interstitial fibrosis in hypertensive heart disease is also associated with elevated expression of these three transcription factors. Deciphering the embryonic pathways of epicardial development has been also an area of interest in regenerative medicine, since tissue repair can be reportedly achieved by reactivation of processes involved in tissue development (Duffey and Smart, ). Therefore, broadening our knowledge on the embryonic pathways that lead to PE and epicardium formation may help develop novel treatments for use in cardiovascular disorders and regenerative medicine.…”