Immunomodulatory Effects of Cell Therapy after Myocardial Infarction

Myocardial infarction (MI) due to coronary artery stenosis compromises vascular endothelial integrity and increases vascular permeability [1,2]. Concurrently, ensuing myocardial tissue death and necrosis results in the release of danger associated molecular patterns (DAMPs), cytokines, chemokines, bioactive lipids, as well as activation of the complement cascade [1-3]. Collectively, these events direct a pronounced and immediate immune response, which includes the recruitment of peripheral blood leukocytes to the site of injury [2,3]. These infiltrating neutrophils are primarily responsible for the clearance of necrotic tissue and cellular debris in ischemic regions via their release of a host of proteolytic enzymes/proteases. While this constitutes a necessary early step in the myocardial repair process at the site of injury, neutrophil-derived reactive oxygen species (ROS) and pro-inflammatory cytokines/chemokines can contribute to collateral damage of surviving myocardium and amplify tissue injury [3,4]. Nevertheless, neutrophils are imperative for proper infarct healing as their depletion prior to MI leads to a dysregulated immune response, excessive scarring, and impaired ventricular function [5]. Within days of an MI, neutrophils undergo cell death and disappear from infarcted tissue [3,4]. Recruitment of neutrophils is followed by two waves of monocyte infiltration. First, early recruitment of Ly6CHigh monocytes expressing pro-inflammatory cytokines, and second, infiltration of Ly6CLow monocytes with pro-resolving and pro-reparative function [3,6,7]. Ly6CHigh monocyte migration is driven by the presence of tissue CCL2 chemokine gradients and their interaction with their cognate receptor, CCR2 [8]—a group of monocytes that are principally sourced from bone marrow and spleen. Subsequently, these monocytes differentiate into Ly6CLowCCR2High macrophages, known as monocyte-derived macrophages [9,10]. These are distinct from Ly6CLowCCR2Low macrophages deposited in the myocardial tissue during embryonic development [11-13]. Both macrophage populations (Ly6CLowCCR2High and Ly6CLowCCR2Low) contribute to myocardial repair by clearance of dead tissue via efferocytosis and production of pro-reparative and pro-resolving mediators. Macrophagederived cytokines play an essential role in the proliferation and activation of cardiac fibroblasts (fibroblast-myofibroblast conversion) that deposit collagen at the site of injury. This process of scar formation fulfills the immediate need to preserve the structural integrity