Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems

Abstract

Innate and adaptive leukocytes rapidly mobilize to ischemic tissues after myocardial infarction in response to damage signals released from necrotic cells. Leukocytes play important roles in cardiac repair and regeneration such as inflammation initiation and resolution; the removal of dead cells and debris; the deposition of the extracellular matrix and granulation tissue; supporting angiogenesis and cardiomyocyte proliferation; and fibrotic scar generation and resolution. By organizing and comparing the present knowledge of leukocyte recruitment and function after cardiac injury in non-regenerative to regenerative systems, we propose that the leukocyte response to cardiac injury differs in non-regenerative adult mammals such as humans and mice in comparison to cardiac regenerative models such as neonatal mice and adult zebrafish. Specifically, extensive neutrophil, macrophage, and T-cell persistence contributes to a lengthy inflammatory period in non-regenerative systems for adverse cardiac remodeling and heart failure development, whereas their quick removal supports inflammation resolution in regenerative systems for new contractile tissue formation and coronary revascularization. Surprisingly, other leukocytes have not been examined in regenerative model systems. With this review, we aim to encourage the development of improved immune cell markers and tools in cardiac regenerative models for the identification of new immune targets in non-regenerative systems to develop new therapies.

Keywords: cardiac injury; heart; humans; immune cells; inflammatory; leukocyte; mice; myocardial infarction; regeneration; repair; zebrafish.

Figure 1

Comparison of cardiac tissue repair in non-regenerative vs. regenerative systems. Schematic demonstrating the three phases (inflammatory, proliferative, and maturation) of heart tissue repair in humans after myocardial infarction or in animal models after cardiac injury. All systems undergo rapid inflammatory phases, but differences occur in the duration of this phase in non-regenerative vs. regenerative model systems. Extensive inflammation (weeks to months) observed in adult mice and humans contributes to permanent scar formation and heart remodeling, eventually leading to heart failure and death. Complete cardiac regeneration occurs in neonatal mice (21 days) and zebrafish (60 days) models with timely resolution of the inflammatory phase (within 1 week) before scar formation in the proliferative phase and then scar resolution in the maturation phase with cardiomyocyte proliferation and angiogenesis. Created with BioRender.com (accessed on 8 February 2022).

Figure 2

Leukocyte recruitment after cardiac injury in non-regenerative vs. regenerative animal model systems. Schematic of immune cell mobilization in myocardial infarction injury models after left anterior descending (LAD) coronary artery ligation in non-regenerative adult mice (upper) and cryoinjury in regenerative adult zebrafish (lower). Adult mice schematic adapted from previously published data [58,125,126]. Adult zebrafish schematic adapted from previously published data [68]. No injury represents steady-state levels of leukocytes without heart injury; hpi stands for hours post-injury; dpi stands for day(s) post-injury. At present, basophils, dendritic cells, natural killer cells, and B cells have no specific marker or antibody to label these cells in the zebrafish model which explains the lack of these cell types in the representative schematic. Created with BioRender.com (accessed on 8 February 2022).