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      Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium

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          Abstract

          Our previous study demonstrated the beneficial effects of exosomes secreted by cardiac mesenchymal stem cells (C-MSC-Exo) in protecting acute ischemic myocardium from reperfusion injury. Here, we investigated the effect of exosomes from C-MSC on angiogenesis in ischemic myocardium. We intramyocardially injected C-MSC-Exo or PBS into the infarct border zone after induction of acute mouse myocardial infarction (MI). We observed that hearts treated with C-MSC-Exo exhibit improved cardiac function compared to control hearts treated with PBS at one month after MI. Capillary density and Ki67-postive cells were significantly higher following treatment with C-MSC-Exo as compared with PBS. Moreover, C-MSC-Exo treatment increased cardiomyocyte proliferation in infarcted hearts. In conclusion, intramyocardial delivery of C-MSC-Exo after myocardial infarction enhances cardiac angiogenesis, promotes cardiomyocyte proliferation, and preserves heart function. C-MSC-Exo constitute a novel form of cell-free therapy for cardiac repair.

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          Most cited references 48

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          Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

          c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. University of Louisville Research Foundation and National Institutes of Health. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.

            Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov, NCT00893360. Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model.

              Mesenchymal stem cells (MSCs) have been increasingly tested experimentally and clinically for cardiac repair. However, the underlying mechanisms remain controversial due to the poor viability and considerable death of the engrafted cells in the infracted myocardium. Recent reports have suggested that extracellular vesicles (EVs) released by MSCs have angiogenesis-promoting activity; however, the therapeutic effect of MSC-EVs on an ischemic heart is unclear. In the present study, we reported that MSCs could release a large quantity of EVs around 100 nm in diameter upon hypoxia stimulation though the majority of the cells had not experienced apoptosis. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells, and the internalization resulted in dose-dependent enhancement of in vitro proliferation, migration, and tube formation of endothelial cells. Using an acute myocardial infarction rat model, we found that intramyocardial injection of MSC-EVs markedly enhanced blood flow recovery, in accordance with reduced infarct size and preserved cardiac systolic and diastolic performance compared to those treated with PBS. These data suggest that like MSCs, MSC-EVs could also protect cardiac tissue from ischemic injury at least by means of promoting blood vessel formation, though further detailed investigations should be performed to define the functionality of MSC-EVs. MSCs released extracellular vesicles (EVs) upon hypoxia stimulation. MSC-EVs were a mixture of microvesicles and exosomes. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells. MSC-EVs promoted neoangiogenesis in vitro and in vivo. MSC-EVs preserved cardiac performance in an AMI model.
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                Author and article information

                Journal
                Journal of Cardiovascular Translational Research
                J. of Cardiovasc. Trans. Res.
                Springer Science and Business Media LLC
                1937-5387
                1937-5395
                October 2018
                September 19 2018
                October 2018
                : 11
                : 5
                : 420-428
                Article
                10.1007/s12265-018-9822-0
                6212335
                30232729
                © 2018

                http://www.springer.com/tdm

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