Author + information
- Received April 11, 2013
- Revision received July 10, 2013
- Accepted July 24, 2013
- Published online November 12, 2013.
- Tamar Ben-Mordechai, PhD∗,
- Radka Holbova, MS∗,
- Natalie Landa-Rouben, PhD∗,
- Tamar Harel-Adar, PhD†,
- Micha S. Feinberg, MD∗,
- Ihab Abd Elrahman, PhD‡,
- Galia Blum, PhD‡,
- Fred H. Epstein, PhD§,
- Zmira Silman, MA∗,
- Smadar Cohen, PhD† and
- Jonathan Leor, MD∗∗ ()
- ∗Neufeld Cardiac Research Institute, Tel Aviv University, Sheba Center for Regenerative Medicine, Stem Cells, and Tissue Engineering, and Tamman Cardiovascular Research Institute, Tel Aviv, Israel
- †Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University, Beer-Sheva, Israel
- ‡Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Campus Ein Karem, Hebrew University, Jerusalem, Israel
- §Departments of Radiology and Biomedical Engineering, University of Virginia, Charlottesville, Virginia
- ↵∗Reprint requests and correspondence:
Dr. Jonathan Leor, Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel.
Objectives This study sought to investigate the hypothesis that the favorable effects of mesenchymal stromal cells (MSCs) on infarct repair are mediated by macrophages.
Background The favorable effects of MSC therapy in myocardial infarction (MI) are complex and not fully understood.
Methods We induced MI in mice and allocated them to bone marrow MSCs, mononuclear cells, or saline injection into the infarct, with and without early (4 h before MI) and late (3 days after MI) macrophage depletion. We then analyzed macrophage phenotype in the infarcted heart by flow cytometry and macrophage secretome in vitro. Left ventricular remodeling and global and regional function were assessed by echocardiography and speckle-tracking based strain imaging.
Results The MSC therapy significantly increased the percentage of reparative M2 macrophages (F4/80+CD206+) in the infarcted myocardium, compared with mononuclear- and saline-treated hearts, 3 and 4 days after MI. Macrophage cytokine secretion, relevant to infarct healing and repair, was significantly increased after MSC therapy, or incubation with MSCs or MSC supernatant. Significantly, with and without MSC therapy, transient macrophage depletion increased mortality 30 days after MI. Furthermore, early macrophage depletion produced the greatest negative effect on infarct size and left ventricular remodeling and function, as well as a significant incidence of left ventricular thrombus formation. These deleterious effects were attenuated with macrophage restoration and MSC therapy.
Conclusions Some of the protective effects of MSCs on infarct repair are mediated by macrophages, which are essential for early healing and repair. Thus, targeting macrophages could be a novel strategy to improve infarct healing and repair.
This project was supported by grants from the Legacy Heritage Fund of New York (Jonathan Leor, Tamar Ben-Mordechai); the Israel Ministry of Science, Culture, and Sport (Jonathan Leor, Smadar Cohen); the Seventh Framework Program, European Commission-Cardiovascular Disease (Jonathan Leor, Smadar Cohen); and the US-Israel Bi-national Science Foundation (Jonathan Leor, Fred H. Epstein). This work was also supported in part by grants from the Israeli National Nanotechnology Initiative and Helmsley Charitable Trust for a focal technology area on nanomedicines for personalized theranostics (Jonathan Leor, Galia Blum). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received April 11, 2013.
- Revision received July 10, 2013.
- Accepted July 24, 2013.
- American College of Cardiology Foundation