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

Figure 1

Transplantation of stem cells vs initiation of endogenous myocardial regeneration without cell transplantation. Depicted are two basic approaches to myocardial regeneration: (1) via transplantation of different types of stem cells into the damaged myocardium (on the left, in blue); and (2) by activation of endogenous pathways of cardiac repair, without cell transplantation (on the right, in red). Both sets of techniques are thought to ultimately exert their effects on the paracrine route and by replenishing lost cardiomyocytes. SCs: Stem cells; BMSCs: Bone marrow-derived stem cells; CPCs: Cardiac progenitor cells; VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factor; G-CSF: Granulocyte colony stimulating factor; EPO: Erythropoietin; GMT: Gata4, Mef2c, Tbx5; miRNAs: microRNAs; PICSO: Pressure-controlled intermittent coronary sinus occlusion.

Figure 2

Hypothesis of embryonic recall. In embryos, the first heart beat is sensed by mechanotransduction of the endocardium, leading to a burst of developmental signals thriving cardiac morphogenesis. In analogy, elevated pressures in cardiac veins act via stretch and shear stress on perivascular cells, thus reiterating the same mechanotransductory signals in the adult failing heart. Pressure elevation in cardiac veins have to be pressure controlled not to increase arterial resistance to nutritive flow (PICSO).