Naftali-Shani N.,Tamman Cardiovascular Research Institute
Journal of the American Heart Association | Year: 2013
Human mesenchymal stromal cells (hMSCs) from adipose cardiac tissue have attracted considerable interest in regard to cell-based therapies. We aimed to test the hypothesis that hMSCs from the heart and epicardial fat would be better cells for infarct repair. We isolated and grew hMSCs from patients with ischemic heart disease from 4 locations: epicardial fat, pericardial fat, subcutaneous fat, and the right atrium. Significantly, hMSCs from the right atrium and epicardial fat secreted the highest amounts of trophic and inflammatory cytokines, while hMSCs from pericardial and subcutaneous fat secreted the lowest. Relative expression of inflammation- and fibrosis-related genes was considerably higher in hMSCs from the right atrium and epicardial fat than in subcutaneous fat hMSCs. To determine the functional effects of hMSCs, we allocated rats to hMSC transplantation 7 days after myocardial infarction. Atrial hMSCs induced greatest infarct vascularization as well as highest inflammation score 27 days after transplantation. Surprisingly, cardiac dysfunction was worst after transplantation of hMSCs from atrium and epicardial fat and minimal after transplantation of hMSCs from subcutaneous fat. These findings were confirmed by using hMSC transplantation in immunocompromised mice after myocardial infarction. Notably, there was a correlation between tumor necrosis factor-α secretion from hMSCs and posttransplantation left ventricular remodeling and dysfunction. Because of their proinflammatory properties, hMSCs from the right atrium and epicardial fat of cardiac patients could impair heart function after myocardial infarction. Our findings might be relevant to autologous mesenchymal stromal cell therapy and development and progression of ischemic heart disease. Source
Leor J.,Tamman Cardiovascular Research Institute |
Leor J.,Tel Aviv University |
Leor J.,Sheba Center for Regenerative Medicine |
Palevski D.,Tamman Cardiovascular Research Institute |
And 9 more authors.
Seminars in Cell and Developmental Biology | Year: 2016
One of the most ambitious goals in modern cardiology is to regenerate the injured myocardium. The human myocardium has poor regenerative power. Thus, significant myocardial injury results in irreversible damage, scar formation, remodeling, and dysfunction. The search for therapies that will improve myocardial regeneration needs a better understanding of the mechanisms of repair and regeneration. While the role of macrophages in inflammation, scar formation, and fibrosis are well defined, their role in myocardial regeneration is less clear. Recent reports have suggested that cardiac macrophages regulate myocardial regeneration in neonatal mice. The present review aims to describe the latest discoveries about the possible role of macrophages in myocardial regeneration. We discuss the promises and difficulties to translate the latest findings into new therapies. © 2016 Elsevier Ltd. Source
Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: Cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure
Madonna R.,University of Chieti Pescara |
Madonna R.,Texas Heart Institute |
Van Laake L.W.,University Utrecht |
Davidson S.M.,University College London |
And 18 more authors.
European Heart Journal | Year: 2016
Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair. © The Author 2016. Source
Kain D.,Tamman Cardiovascular Research Institute |
Kain D.,Tel Aviv University |
Kain D.,Sheba Center for Regenerative Medicine |
Amit U.,Tamman Cardiovascular Research Institute |
And 23 more authors.
International Journal of Cardiology | Year: 2016
Background Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling. Methods and results We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p < 0.05), and reduced cardiac fibrosis by 75%, compared with controls (p = 0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p < 0.05), and a 13% in LV mass (p = 0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p = 0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%). Conclusions Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease. © 2015 Elsevier Ireland Ltd. All rights reserved. Source
Ben-Mordechai T.,Tel Aviv University |
Ben-Mordechai T.,Tamman Cardiovascular Research Institute |
Ben-Mordechai T.,Sheba Center for Regenerative Medicine |
Palevski D.,Tel Aviv University |
And 8 more authors.
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2015
Macrophages are involved in every cardiovascular disease and are an attractive therapeutic target. Macrophage activation is complex and can be either beneficial or deleterious, depending upon its mode of action, its timing, and its duration. An important macrophage characteristic is its plasticity, which enables it to switch from one subset to another. Macrophages, which regulate healing and repair after myocardial infarction, have become a major target for both treatment and diagnosis (theranostic). The aim of the present review is to describe the recent discoveries related to targeting and modulating of macrophage function to improve infarct repair.We will briefly review macrophage polarization, plasticity, heterogeneity, their role in infarct repair, regeneration, and cross talk with mesenchymal cells. Particularly, we will focus on the potential of macrophage targeting in situ by liposomes. The ability to modulate macrophage function could delineate pathways to reactivate the endogenous programs of myocardial regeneration. This will eventually lead to development of small molecules or biologics to enhance the endogenous programs of regeneration and repair. © The Author(s) 2014. Source