Abstract 4: Lymphatic Vessels Mediate the Mobilization of Cardiac Progenitor Cells after Myocardial Infarction

Abstract

The delivery of adult cardiac progenitor cells (CPCs) or their activation in situ constitute an evolving approach for the treatment of heart failure. CPCs are endowed with regenerative capacity, producing differentiating myocytes and vascular structures in the course of homeostasis and upon injury. The regenerative function of CPCs is contingent to their ability to migrate to and engraft within the wounded area. Yet, the mechanisms governing CPC trafficking in the diseased myocardium are largely unknown. The lymphatic system is vital for tissue repair, and the role of the lymphatic vasculature in the trafficking of hematopoietic and cancer cells is well documented. We examined whether cardiac lymphatic vessels mediate the translocation of CPCs in the infarcted myocardium. By imaging of the heart from transgenic c-kit-GFP reporter mice, we found that as early as 4 hours after myocardial infarction (MI), uncommitted lineage-negative progenitors accumulated in the vicinity of the lymphatic vessels located in the region bordering the necrotic area. Histologically, extensive lymphangiogenesis was documented in the mouse heart in the acute (8-48 hours) and chronic (15-35 days) phases of infarct healing and scar formation. CPCs were detected traversing the wall of lymphatic vessels at different stages after MI, indicative of the functional role of the lymphatic circulation in the recruitment of primitive cells to the site of injury. Furthermore, isolated human CPCs exhibited chemotaxis and specific binding to the human lymphatic endothelial cells (LECs) in steady-state conditions and, increasingly, after exposure to an inflammatory cytokine, TNFα. CPCs performed trans-endothelial migration in vitro, and actively intravasated into the lumen of microvessels formed by LECs in three-dimensional matrices. Finally, our data suggest that sphingosine-1-phosphate (S1P)-stimulated signaling governs the interactions of CPCs with LECs. These findings on the direct role of lymphatic vasculature in CPC trafficking may contribute to the development of novel therapeutic modalities to increase mobilization of endogenous or transplanted CPCs, promoting myocardial repair in patients with ischemic heart diseases.