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.
Metrics
-
- 3,053
- Page views
-
- 512
- Downloads
-
- 43
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
eLife 9:e57920.
https://doi.org/10.7554/eLife.57920
Further reading
-
- Immunology and Inflammation
Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.
-
- Developmental Biology
- Immunology and Inflammation
During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
