Contemporary perspective on endogenous myocardial regeneration

Abstract

Considering the complex nature of the adult heart, it is no wonder that innate regenerative processes, while maintaining adequate cardiac function, fall short in myocardial jeopardy. In spite of these enchaining limitations, cardiac rejuvenation occurs as well as restricted regeneration. In this review, the background as well as potential mechanisms of endogenous myocardial regeneration are summarized. We present and analyze the available evidence in three subsequent steps. First, we examine the experimental research data that provide insights into the mechanisms and origins of the replicating cardiac myocytes, including cell populations referred to as cardiac progenitor cells (i.e., c-kit+ cells). Second, we describe the role of clinical settings such as acute or chronic myocardial ischemia, as initiators of pathways of endogenous myocardial regeneration. Third, the hitherto conducted clinical studies that examined different approaches of initiating endogenous myocardial regeneration in failing human hearts are analyzed. In conclusion, we present the evidence in support of the notion that regaining cardiac function beyond cellular replacement of dysfunctional myocardium via initiation of innate regenerative pathways could create a new perspective and a paradigm change in heart failure therapeutics. Reinitiating cardiac morphogenesis by reintroducing developmental pathways in the adult failing heart might provide a feasible way of tissue regeneration. Based on our hypothesis “embryonic recall”, we present first supporting evidence on regenerative impulses in the myocardium, as induced by developmental processes.

Keywords: Cardiac regeneration; Cardiac development; Embryonic recall; Pressure-controlled intermittent coronary sinus occlusion; Heart failure; Myocardial infarction

Core tip: Unlike in primitive vertebrates, any regenerative effort in adult mammalian hearts after an acute event remains unsatisfactory. Most efforts to repopulate failing hearts with functioning and integrated cardiomyocytes have not achieved clinical importance. In this overview, after describing several options for endogenous myocardial repair, we support the notion of a paradigm change towards inducible developmental processes in regeneration research. Major efforts have been made to convert tissues upstream in the Waddington scheme. Recently, stress transformed acquired pluripotency raised enormous expectations, but results and proof of concept were seriously questioned. We want to introduce pressure-controlled intermittent coronary sinus occlusion as a potential resource to decipher the unsolved equation of re-inducing the developmental processes in the human heart.