Characterization of the Scarification and Neolymphangiogenesis in Experimental Mouse Model of Acute and Chronic Myocardial Infarction: the Dual Role of Podoplanin Expressing Cells

Characterization of the cellular composition of the scar after myocardial infarction (MI) is poorly investigated; new insights in the biology of wound healing and inflammation post MI may establish undiscovered interactome in the infarcted heart that will lead new approaches for cardioprotective or regenerative therapies. Using a mouse model of permanent coronary artery ligation, we examined spatiotemporal changes in the expression of endothelial, lymphendothelial and mesenchymal markers in the acutely and chronically infarcted myocardium in order to analyze the cellular composition of the scar. We found that at the time of wound granulation, a three-fold increase in the frequency of podoplanin-labeled cells occurred in the infarcted hearts compared to non-operated and sham-operated counterparts. Podoplanin immunoreactivity detected LYVE-1-positive lymphatic vessels, as well as masses of LYVE-1-negative cells dispersed between myocytes, predominantly in the vicinity of the infarcted region. Podoplanin-carrying populations displayed a mesenchymal progenitor marker PDGFRα, and intermittently expressed Prox-1, a master regulator of the lymphatic endothelial fate. At the stages of scar formation and maturation, concomitantly with the enlargement of lymphatic network in the injured myocardium, the podoplanin-rich LYVE-1-negative multicellular assemblies were apparent in the fibrotic area, aligned with extracellular matrix deposits, or located in immediate proximity to activated blood vessels with high VEGFR-2 content. Of note, these podoplanin-containing cells acquired the expression of PDGFRβ or a hematoendothelial epitope CD34. Although Prox-1 labeling was abundant in the area affected by MI, the podoplanin-presenting cells were not consistently Prox-1-positive. The concordance of podoplanin with VEGFR-3 similarly varied. The role of podoplanin in the healing heart was never investigate, our data reveal previously unknown phenotypic and structural heterogeneity within the podoplanin-positive cell compartment in the infarcted heart, and suggest an alternate ability of podoplanin-presenting cardiac cells to generate lymphatic endothelium and pro-fibrotic cells, contributing to scar development.