Abstract 12083: Lymphatic Vasculature Mediates Cardiac Progenitor Cell Trafficking After Myocardial Infarction

Abstract

Myocardial infarction (MI) and post-MI heart failure are major causes of morbidity and mortality. Cardiac progenitor cells (CPC) regenerate injured myocardium, due to their ability to migrate and engraft in the wounded area. Yet, the mechanisms governing CPC trafficking in the diseased myocardium are largely unknown. We examined a hitherto unaddressed role of cardiac lymphatic microvessels (LMV) in CPC mobilization to the site of infarction. We detected that in acute and chronic MI, mouse CPC accumulated in the infarct border zone in proximity of LMV and traversed their wall. We showed that human CPC actively intravasated into the lumen of three-dimensional LMV formed by human lymphatic endothelial cells (LEC) in vitro. The binding of CPC to LEC was hindered in the presence of N-cadherin inhibitory peptide or E-selectin neutralizing antibody. CPC displayed unique pattern of interactions with LEC. Specifically, the propensity of CPC to adhere to LEC at basal conditions and after pre-stimulation with an inflammatory mediator TNFα was higher comparing to human cardiac microvascular endothelial cells (CMEC). Trans-migration of CPC through LEC but not CMEC monolayer was enhanced following treatment with TNFα. Interference with the SDF-1/CXCR4 pathway diminished CPC intravasation via LEC but did not affect the CPC ability to traverse CMEC. Intriguingly, we found that the bioactive lipid S1P, secreted by endothelial cells, had a significant impact on CPC migration. S1P binds to 5 different S1P receptors (S1P1-5). We established that the expression of S1P3 was enriched in CPC. Although exposure to S1P mitigated CPC motility, an S1P3-selective agonist evoked strong chemotaxis of CPC, whereas down-regulation of S1P3 blocked CPC translocation. Accordingly, CPC activation with S1P3 agonist reduced their contacts with the extracellular matrix, while S1P ligand induced the organization of adhesion complexes containing β1-integrin subunit. The direct role of S1P3 in CPC trafficking in vivo is supported by our observations that S1P3 expression was increased in the cardiac cells associated with LMV after MI. In conclusion, we provide evidence that specific interactions with LMV may promote CPC trafficking in the infarcted heart facilitating myocardial repair.