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      Intramyocardial Injection of Autologous Bone Marrow-Derived Ex Vivo Expanded Mesenchymal Stem Cells in Acute Myocardial Infarction Patients is Feasible and Safe up to 5 Years of Follow-up

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          Abstract

          In experimental studies, mesenchymal stem cell (MSC) transplantation in acute myocardial infarction (AMI) models has been associated with enhanced neovascularization and myogenesis. Clinical data however, are scarce. Therefore, the present study evaluates the safety and feasibility of intramyocardial MSC injection in nine patients, shortly after AMI during short-term and 5-year follow-up. Periprocedural safety analysis demonstrated one transient ischemic attack. No other adverse events related to MSC treatment were observed during 5-year follow-up. Clinical events were compared to a nonrandomized control group comprising 45 matched controls. A 5-year event-free survival after MSC-treatment was comparable to controls (89 vs. 91 %, P = 0.87). Echocardiographic imaging for evaluation of left ventricular function demonstrated improvements up to 5 years after MSC treatment. These findings were not significantly different when compared to controls. The present safety and feasibility study suggest that intramyocardial injection of MSC in patients shortly after AMI is feasible and safe up to 5-year follow-up.

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          Most cited references 23

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          A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

          Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).
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            Cardiomyocytes can be generated from marrow stromal cells in vitro.

            We have isolated a cardiomyogenic cell line (CMG) from murine bone marrow stromal cells. Stromal cells were immortalized, treated with 5-azacytidine, and spontaneously beating cells were repeatedly screened. The cells showed a fibroblast-like morphology, but the morphology changed after 5-azacytidine treatment in approximately 30% of the cells; they connected with adjoining cells after one week, formed myotube-like structures, began spontaneously beating after two weeks, and beat synchronously after three weeks. They expressed atrial natriuretic peptide and brain natriuretic peptide and were stained with anti-myosin, anti-desmin, and anti-actinin antibodies. Electron microscopy revealed a cardiomyocyte-like ultrastructure, including typical sarcomeres, a centrally positioned nucleus, and atrial granules. These cells had several types of action potentials, such as sinus node-like and ventricular cell-like action potentials. All cells had a long action potential duration or plateau, a relatively shallow resting membrane potential, and a pacemaker-like late diastolic slow depolarization. Analysis of the isoform of contractile protein genes, such as myosin heavy chain, myosin light chain, and alpha-actin, indicated that their muscle phenotype was similar to that of fetal ventricular cardiomyocytes. These cells expressed Nkx2.5/Csx, GATA4, TEF-1, and MEF-2C mRNA before 5-azacytidine treatment and expressed MEF-2A and MEF-2D after treatment. This new cell line provides a powerful model for the study of cardiomyocyte differentiation.
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              Immunomodulation by mesenchymal stem cells and clinical experience.

               Tung Le,  Olle Ringden (2007)
              Mesenchymal stem cells (MSCs) from adult marrow can differentiate in vitro and in vivo into various cell types, such as bone, fat and cartilage. MSCs preferentially home to damaged tissue and may have therapeutic potential. In vitro data suggest that MSCs have low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes. Instead, MSCs appear to be immunosuppressive in vitro. They inhibit T-cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic T-cells. In vivo, MSCs prolong skin allograft survival and have several immunomodulatory effects, which are presented and discussed in the present study. Possible clinical applications include therapy-resistant severe acute graft-versus-host disease, tissue repair, treatment of rejection of organ allografts and autoimmune disorders.
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                Author and article information

                Contributors
                +31-71-5262020 , +31-71-5266809 , d.e.atsma@lumc.nl
                Journal
                J Cardiovasc Transl Res
                J Cardiovasc Transl Res
                Journal of Cardiovascular Translational Research
                Springer US (Boston )
                1937-5387
                1937-5395
                28 August 2013
                28 August 2013
                2013
                : 6
                : 816-825
                Affiliations
                [ ]Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333, Post office box 9600, 2300 RC Leiden, The Netherlands
                [ ]Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
                [ ]Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
                [ ]Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands
                [ ]Jon J. van Rood Center for Clinical Transfusion Research, Sanquin, Leiden University Medical Center, Leiden, The Netherlands
                Author notes

                Associate Editor Lorrie Kirshenbaum oversaw the review of this article

                Article
                9507
                10.1007/s12265-013-9507-7
                3790917
                23982478
                © The Author(s) 2013

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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                © Springer Science+Business Media New York 2013

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