Author + information
- Received September 10, 2019
- Accepted October 6, 2019
- Published online December 16, 2019.
- Nezam Haider, MD, PhDa,b,∗,
- Lisardo Boscá, PhDc,d,∗∗ (, )@LubbDup@CNIC_CARDIO,
- H. Reinier Zandbergen, MD, PhDe,∗,
- Jason C. Kovacic, MD, PhDa,
- Navneet Narula, MD, PhDf,
- Silvia González-Ramos, PhDc,d,
- María Fernandez-Velasco, PhDd,g,
- Sudhanshu Agrawal, SCYM(ASPC)h,
- Marta Paz-García, MScc,
- Sudhir Gupta, MD, PhDh,
- Kristine DeLeon-Pennell, PhDi,
- Valentin Fuster, MD, PhDa,j,
- Borja Ibañez, MD, PhDd,j,k@Borjaibanez1 and
- Jagat Narula, MD, PhDa
- aZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bDivision of Vascular Surgery, University of Arizona, Tucson, Arizona
- cInstituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid, Spain
- dCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Melchor Fernández Almagro, Madrid, Spain
- eDepartment of Cardiothoracic Surgery, Amsterdam University Medical Center, Amsterdam, the Netherlands
- fDepartment of Pathology, New York University Langone Medical Center, New York, New York
- gInstituto de Investigación Biomédica LaPaz, Paseo de la Castellana, Madrid, Spain
- hDivision of Basic and Clinical Immunology, University of California, Irvine, California
- iDivision of Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- jCentro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- kInstituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
- ↵∗Address for correspondence:
Dr. Lisardo Boscá, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid, Spain.
Background Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.
Objectives This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.
Methods Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.
Results Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI.
Conclusions The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
- cardiac fibroblast
- fibroblast markers
- macrophage/fibroblast-like transition
- myeloid tracers
- myocardial infarction
↵∗ Drs. Haider, Boscá, and Zandbergen contributed equally to this work.
This work was supported by grants SAF2017-82436R and RTC2017-6283 from MINEICO, S2017/BMD-3686 from Comunidad de Madrid, CIVP18A3864 from Fundación Ramón Areces and CIBERCV (funded by the Instituto de Salud Carlos III), Fondos FEDER, and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award IK2BX003922 (to Dr. DeLeon-Pennell). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Peter Libby, MD, served as Guest Associate Editor for this paper.
- Received September 10, 2019.
- Accepted October 6, 2019.
- 2019 American College of Cardiology Foundation
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