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.
Highlights
Cardiovascular disease (CVD) persists as the primary disease burden in the UnitedStates, with nearly 659,000 people dying each year and costing 363 billion USD [1,2]
During myocardial infarction (MI), ischemic myocardial fibers become necrotic and release damageassociated molecular patterns (DAMPs) and alarmins [3]. These molecules rapidly mobilize an arsenal of inflammatory leukocytes such as neutrophils, monocytes/macrophages, and dendritic cells to the ischemic area for the removal of dead cells and cellular debris, and disintegration of the extracellular matrix (ECM)
As recent studies demonstrated low rates of cardiomyocyte renewal throughout life in humans and cardiac regeneration capabilities in mammalian neonates [9–14], researchers are actively searching for factors capable of stimulating endogenous regeneration mechanisms in humans by examining innate regenerative responses in other vertebrate animal models, such as zebrafish and neonatal mice [15–17]
Summary
Cardiovascular disease (CVD) persists as the primary disease burden in the United. States, with nearly 659,000 people dying each year and costing 363 billion USD [1,2]. During myocardial infarction (MI), ischemic myocardial fibers become necrotic and release damageassociated molecular patterns (DAMPs) and alarmins [3]. These molecules rapidly mobilize an arsenal of inflammatory leukocytes such as neutrophils, monocytes/macrophages, and dendritic cells to the ischemic area for the removal of dead cells and cellular debris, and disintegration of the extracellular matrix (ECM). Macrophages clear apoptotic neutrophils to induce inflammation resolution and support the transition to a proliferative phase [4]. During this phase, myofibroblasts generate granulation tissue, and endothelial cells differentiate to form new blood vessels [5].
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