Tamman Cardiovascular Research Institute

Tel Aviv, Israel

Tamman Cardiovascular Research Institute

Tel Aviv, Israel
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Perrino C.,University of Naples Federico II | Barabasi A.-L.,Northeastern University | Barabasi A.-L.,Dana-Farber Cancer Institute | Barabasi A.-L.,Central European University | And 30 more authors.
Cardiovascular Research | Year: 2017

Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human ‘diseasome’. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.


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.


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.


Rinkevich-Shop S.,Tamman Cardiovascular Research Institute | Rinkevich-Shop S.,Regenerative Medicine Stem Cells and Tissue Engineering Center | Rinkevich-Shop S.,Tel Aviv University | Konen E.,Sheba Medical Center | And 16 more authors.
European Heart Journal Cardiovascular Imaging | Year: 2013

AimsThe aim of this study was to assess the use of a 3 T clinical cardiac magnetic resonance (CMR) scanner to detect injury to the heart in experimental autoimmune myocarditis (EAM).Methods and resultsThe use of 3 T CMR for the detection of cardiac injury was assessed in EAM (n = 55) and control (n = 10) male Lewis rats. Animals were evaluated with serial CMR imaging studies, using a 3 T scanner, and with 2D echocardiography before, and at 2 and 5 weeks after EAM induction. By CMR, regional wall motion abnormalities were noted in seven out of eight rats with myocarditis 5 weeks after induction. Subsequently, the rats developed significant left ventricular (LV) dilatation, wall thickening, and pericardial effusion. Average LV systolic and diastolic volumes increased from 131 ± 10 to 257 ± 20 μL (P = 0.0008), and from 309 ± 14 to 412 ± 24 μL (P < 0.0001), and ejection fraction markedly deteriorated (from 58 ± 2 to 37 ± 5%; P = 0.0003). Areas of fibrosis were located by late gadolinium enhancement (LGE) CMR at the subepicardium, mainly within the anterior, lateral, and inferior walls. The extent and location of LGE were highly correlated (r = 0.94; P < 0.0001) with areas of myocardial fibrosis by histopathology, with 85% sensitivity and 86% specificity.ConclusionA clinical 3 T CMR scanner enables accurate detection, quantification, and monitoring of experimental myocarditis in rats, and could be used for translational research to study the pathophysiology of the disease and evaluate novel therapies. © 2013 The Author.


D'Uva G.,Weizmann Institute of Science | Aharonov A.,Weizmann Institute of Science | Lauriola M.,Weizmann Institute of Science | Lauriola M.,University of Bologna | And 18 more authors.
Nature Cell Biology | Year: 2015

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3 2/2-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials. © 2015 Macmillan Publishers Limited.


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.


Adutler-Lieber S.,Tel Aviv University | Adutler-Lieber S.,Stem Cell and Tissue Engineering Center | Adutler-Lieber S.,Tamman Cardiovascular Research Institute | Ben-Mordechai T.,Tel Aviv University | And 11 more authors.
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2013

Background: Mesenchymal stromal cells (MSCs) improve tissue repair but their mechanism of action is not fully understood. We aimed to test the hypothesis that MSCs may act via macrophages, and that specifically, human cardiac adipose tissue-derived mesenchymal stromal cells (AT-MSCs) can polarize human macrophages into a reparative, anti-inflammatory (M2) phenotype. Methods and Results: We isolated and grew AT-MSCs from human cardiac adipose tissue obtained during cardiac surgery. Macrophages were grown from CD14+ monocytes from healthy donor blood and then cocultured with AT-MSCs, with and without transwell membrane, for 1 to 14 days. In response to AT-MSCs, macrophages acquired a star-shaped morphology, typical of alternatively activated phenotype (M2), and increased the expression of M2 markers CD206 +, CD163+, and CD16+ by 1.5- and 9-fold. Significantly, AT-MSCs modified macrophage cytokine secretion and increased the secretion of anti-inflammatory and angiogenic cytokines: interleukin (IL)-10 (9-fold) and vascular endothelial growth factors (3-fold). Moreover, AT-MSCs decreased macrophage secretion of inflammatory cytokines such as IL-1α (2-fold), tumor necrosis factor α (1.5-fold), IL-17 (3-fold), and interferon gamma (2-fold). Remarkably, the interaction between AT-MSCs and macrophages was bidirectional and macrophages enhanced AT-MSC secretion of typical M2 inducers IL-4 and IL-13. Notably, AT-MSCs decreased macrophage phagocytic capacity. Finally, IL-6 mediates the M2 polarization effect of AT-MSCs on macrophages, by increasing M2-associated cytokines, IL-10 and IL-13. Conclusions: Human cardiac AT-MSCs can polarize human macrophages into anti-inflammatory phenotype. Our findings suggest a new mechanism of action of AT-MSCs that could be relevant to the pathogenesis and treatment of myocardial infarction, atherosclerosis, and various cardiovascular diseases. © 2013 The Author(s).


PubMed | Tamman Cardiovascular Research Institute
Type: Comparative Study | Journal: 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- 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.


PubMed | Tamman Cardiovascular Research Institute
Type: Journal Article | Journal: PloS one | Year: 2016

Irreversible electroporation (IRE) is a non-thermal cell ablation approach that induces selective damage to cell membranes only. The purpose of the current study was to evaluate and optimize its use for in-vivo myocardial decellularization.Forty-two Sprague-Dawley rats were used to compare myocardial damage of seven different IRE protocols with anterior myocardial infarction damage. An in-vivo open thoracotomy model was used, with two-needle electrodes in the anterior ventricular wall. IRE protocols included different combinations of pulse lengths (70 vs. 100 seconds), frequency (1, 2, 4 Hz), and number (10 vs. 20 pulses), as well as voltage intensity (50, 250 and 500 Volts). All animals underwent baseline echocardiographic evaluation. Degree of myocardial ablation was determined using repeated echocardiography measurements (days 7 and 28) as well as histologic and morphometric analysis at 28 days.All animals survived 28 days of follow-up. Compared with 50V and 250V, electroporation with 500V was associated with significantly increased myocardial scar and reduction in ejection fraction (67.4%4% at baseline vs. 34.6%20% at 28 days; p <0.01). Also, compared with pulse duration of 70 sec, pulses of 100 sec were associated with markedly reduced left ventricular function and markedly increased relative scar area ratio (28%9% vs. 16%3%, p = 0.02). Decreasing electroporation pulse frequency (1Hz vs. 2Hz, 2Hz vs. 4Hz) was associated with a significant increase in myocardial damage. Electroporation protocols with a greater number of pulses (20 vs. 10) correlated with more profound tissue damage (p<0.05). When compared with myocardial infarction damage, electroporation demonstrated a considerable likeness regarding the extent of the inflammatory process, but with relatively higher levels of extra-cellular preservation.IRE has a graded effect on the myocardium. The extent of ablation can be controlled by changing pulse length, frequency and number, as well as by changing electric field intensity.


PubMed | Chaim Sheba Medical Center, Weizmann Institute of Science, Tamman Cardiovascular Research Institute, University of Bologna and Victor Chang Cardiac Research Institute
Type: Journal Article | Journal: Nature cell biology | Year: 2015

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3/-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

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