Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.07.240820v1?rss=1 Authors: Alonso-Herranz, L., Sahun-Espanol, A., Gonzalo, P., Gkontra, P., Nunez, V., Cedenilla, M., Villalba-Orero, M., Inserte, J., Clemente, C., Garcia-Dorado, D., Arroyo, A. G., Ricote, M. Abstract: Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP{Delta}LysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGF{beta}1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP{Delta}LysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease. Copy rights belong to original authors. Visit the link for more info