Agrin-Mediated Cardiac Regeneration: Some Open Questions

Abstract

After cardiac injury, the mammalian adult heart has a very limited capacity to regenerate, due to the inability of fully differentiated cardiomyocytes (CMs) to efficiently proliferate. This has been directly linked to the extracellular matrix (ECM) surrounding and connecting cardiomyocytes, as its increasing rigidity during heart maturation has a crucial impact over the proliferative capacity of CMs. Very recent studies using mouse models have demonstrated how the ECM protein agrin might promote heart regeneration through CMs de-differentiation and proliferation. In maturing CMs, this proteoglycan would act as an inducer of a specific molecular pathway involving ECM receptor(s) within the transmembrane dystrophin-glycoprotein complex (DGC) as well as intracellular Yap, an effector of the Hippo pathway involved in the replication/regeneration program of CMs. According to the mechanism proposed, during mice heart development agrin gets progressively downregulated and ultimately replaced by other ECM proteins eventually leading to loss of proliferation/ regenerative capacity in mature CMs. Although the role played by the agrin-DGC-YAP axis during human heart development remains still largely to be defined, this scenario opens up fascinating and promising therapeutic avenues. Herein, we discuss the currently available relevant information on this system, with a view to explore how the fundamental understanding of the regenerative potential of this cellular program can be translated into therapeutic treatment of injured human hearts.

Engineering Extracellular Matrix Proteins to Enhance Cardiac Regeneration After Myocardial Infarction

“…ECM proteins that were applied for myocardial regeneration augmented the additional modification to enhance longevity and contribution for remuscularization (e.g., CorMatrix and VentriGel). ECM proteins binding to αDG, agrin, or Slit-2 contributed to CM proliferation (Bigotti et al, 2020 ), but further mechanistic understanding requires establishing a better strategy for CM proliferation. In addition to providing novel engineering strategies for cardiac repair, more critical analysis of CM proliferation assays and induction of CM proliferation by microRNA, metabolic switch, or small molecule is necessary to inform the field to efficiently reach the goal of myocardial regeneration (Leone and Engel, 2019 ).…”

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

“…This suggested a role of agrin as a modulator of cardiomyocyte differentiation, proliferation, and regeneration in a way that involves YAP signaling. The implications of this exciting discovery have been discussed in more detail in a recent review (Bigotti et al, 2020). Altogether the YAP/TAZ pathway plays a crucial role in cardiac mechanotransduction and is a potent regulator of cell fate and function.…”

Mechanobiological Principles Influence the Immune Response in Regeneration: Implications for Bone Healing

“…For example, agrin mediated signaling has been shown to cause increased actin cytoskeletal rearrangements, with the result that agrin deficiency impaired phagocytosis in macrophages and ultimately the clearance of tissue debris after injury (Mazzon et al, 2012). Adult mammalian hearts generally have a very low regenerative capacity, likely due to the inability of fully differentiated cardiomyocytes to proliferate (Kikuchi and Poss, 2012;Bigotti et al, 2020). Therefore, therapies that promote the proliferation of cardiomyocytes via YAP/TAZ-signaling such as the administration of the ECM-component agrin, are an exciting new approach, whose full potential, including its effect on immune cells, could be the focus of further research.…”