Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction.
Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction.
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DOI：
10.7554/elife.57920
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发表时间：
2020-10-16
期刊：
影响因子：
7.7
通讯作者：
Ricote M
中科院分区：
文献类型：
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作者：
Alonso-Herranz L;Sahún-Español Á;Paredes A;Gonzalo P;Gkontra P;Núñez V;Clemente C;Cedenilla M;Villalba-Orero M;Inserte J;García-Dorado D;Arroyo AG;Ricote M
巨噬细胞（Mφs）产生参与心肌梗死（MI）后心脏修复和重塑的因子;然而，这些因子如何与介导修复的其他细胞类型相互作用尚不完全清楚。我们发现心肌Mφ在MI后7天增加了Mmp 14（MT 1-MMP）的表达。我们使用遗传策略（Mmp 14 f/f：Lyz 2-Cre）选择性地失活Mφ中的Mmp 14基因。这种条件性KO（MAC-Mmp 14 KO）导致MI后心功能障碍减弱，纤维化减少，并保留了心脏毛细血管网络。从机制上讲，我们发现MT 1-MMP激活Mφ中潜伏的TGFβ1，导致内皮细胞（EC）中的旁分泌SMAD 2介导的信号传导和内皮向间充质转化（EndMT）。MI后MAC-Mmp 14 KO心脏比野生型心脏含有更少的经历EndMT的细胞，并且Mmp 14缺陷的Mφ在与EC共培养中显示出诱导EndMT的能力降低。我们的研究结果表明EndMT在心肌梗死后心脏纤维化和不良重构中的作用，并确定Mφ MT 1-MMP是这一过程的关键调节因子。
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.