Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

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-MMPΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMPΔLysM 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.

Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration

“…1A) (2). After cardiac injury, -smooth muscle actin (SMA) + myofibroblasts arise from cardiac fibroblasts and endothelial cells and are the principal contributors to scar-like ECM remodeling (3)(4)(5). Myofibroblasts can further differentiate into more specialized matrifibrocytes to support the mature scar (3).…”

EndMT: New findings on the mechanism underlying fibrosis of intrauterine adhesions

“…The conversion of endothelial cells into broblasts during the EndMT was originally described in the context of experimental wound repair 25 . Endothelial cells have also been reported to contribute to broblast production and aggregation in brotic diseases of the lung, heart, eye, kidney and other organs [26][27][28][29] . The EndMT is characterised by the loss of intercellular junctions between endothelial cells, which acquire an invasive and migratory phenotype and exhibit upregulated expression of mesenchymal cell markers such as alpha-smooth muscle actin (α-SMA), broblast-speci c protein-1 and vimentin.…”