Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction.
Macrophages (Mφs) 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. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.
['Alonso-Herranz|Laura|L|0000-0003-0880-4735', 'Sahún-Español|Álvaro|Á|0000-0003-3833-5386', 'Paredes|Ana|A|0000-0003-3119-8788', 'Gonzalo|Pilar|P|0000-0001-8811-8369', 'Gkontra|Polyxeni|P|', 'Núñez|Vanessa|V|', 'Clemente|Cristina|C|0000-0002-5831-9132', 'Cedenilla|Marta|M|', 'Villalba-Orero|María|M|', 'Inserte|Javier|J|', 'García-Dorado|David|D|', 'Arroyo|Alicia G|AG|0000-0002-1536-3846', 'Ricote|Mercedes|M|0000-0002-8090-8902']
D000818:Animals D003094:Collagen D004195:Disease Models, Animal D004730:Endothelium, Vascular D058750:Epithelial-Mesenchymal Transition D005260:Female D005355:Fibrosis D005434:Flow Cytometry D005786:Gene Expression Regulation D057809:HEK293 Cells D006801:Humans D008264:Macrophages D008297:Male D053511:Matrix Metalloproteinase 14 D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008833:Microcirculation D009203:Myocardial Infarction D010641:Phenotype D015427:Reperfusion Injury D053773:Transforming Growth Factor beta1 D018487:Ventricular Dysfunction, Left
macrophages MT1-MMP myocardial infarction endothelial cells TGFB1 immunology inflammation mouse regenerative medicine stem cells tissue remodeling