Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
- Centro Nacional de Investigaciones Cardiovasculares, Spain
- Vall d'Hebron University Hospital and Research Institute, Spain
- Centro de Investigaciones Biológicas (CIB-CSIC), Spain
Abstract
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 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all the figures.
Article and author information
Author details
Laura Alonso-Herranz
Funding
Spanish Ministry of Science, Innovation and Universities (SAF2017-90604-REDT-NurCaMein)
- Mercedes Ricote
Spanish Ministry of Science, Innovation and Universities (RTI2018-095928-BI00)
- Mercedes Ricote
Spanish Ministry of Science, Innovation and Universities (SAF2017-83229-R)
- Alicia G Arroyo
Comunidad de Madrid (MOIR-B2017/BMD-3684)
- Alicia G Arroyo
La Marato TV3 Foundation
- David García-Dorado
- Alicia G Arroyo
- Mercedes Ricote
Fundacion La Caixa
- Laura Alonso-Herranz
- Álvaro Sahún-Español
La Residencia de Estudiantes
- Álvaro Sahún-Español
FORD-Spain and Apadrina La Ciencia
- Álvaro Sahún-Español
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Noriaki Emoto, Kobe Pharmaceutical University, Japan
Ethics
Animal experimentation: All animal procedures were conducted in accordance with EU Directive 86/609/EEC and approved by the Animal Subjects Committee of the Instituto de Salud Carlos III (Madrid, Spain) and Madrid Community Organs in the PROEX 188/26. All surgery was performed under anesthesia with sevoflurane (5% for induction, 2%-3% for maintenance) and buprenorphine (0.01 mg/kg, Buprex, Merck & Co. Inc) was given for pain relief.
Version history
- Received: April 15, 2020
- Accepted: October 15, 2020
- Accepted Manuscript published: October 16, 2020 (version 1)
- Accepted Manuscript updated: October 21, 2020 (version 2)
- Version of Record published: November 3, 2020 (version 3)
Copyright
© 2020, Alonso-Herranz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
eLife 9:e57920.
https://doi.org/10.7554/eLife.57920
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