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      Arrhythmia Susceptibility in Mice after Therapy with β-Catenin-Transduced Hematopoietic Progenitor Cells after Myocardial Ischemia/Reperfusion

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          Abstract

          Background: Hematopoietic progenitor cells (HPCs) can improve cardiac function after myocardial infarction. However, occurrence of arrhythmias is a potential limitation of cell therapy. In this study, we investigated the cardiac electrophysiological properties of ex vivo expanded HPCs, generated by β-catenin gene transfer, after transcoronary delivery in a murine model of ischemia/reperfusion (I/R) injury. Methods and Results: To assess arrhythmia inducibility of ex vivo expanded HPCs, mice were subjected to I/R and assigned to sham operation (n = 8), I/R (n = 21) and HPC (n = 15) treatment. Six weeks later, mice were subjected to long-term electrocardiogram recording and in vivo transvenous electrophysiological study. After I/R, mice showed a significant prolongation of conduction and repolarization compared with sham-operated mice. There was a marked increase in ventricular ectopic activity in infarcted mice as compared with sham-operated mice. Cardiac electrophysiological parameters and ventricular ectopic activity were not altered in mice treated with HPCs in comparison with control I/R mice. Conclusion: Transcoronary delivery of genetically ex vivoexpanded HPCs did not alter the electrophysiological properties in mice after I/R. Therefore, ex vivo β-catenin-mediated HPC expansion may represent an attractive therapeutic option for cell transplantation treatment of myocardial infarction without electrophysiological side effects.

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          Most cited references 23

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          Mobilized bone marrow cells repair the infarcted heart, improving function and survival.

          Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin(-) c-kit(POS) BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokine-induced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 x 10(6) new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.
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            Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling.

            In this study, we hypothesized that bone marrow stem cells (BMSCs) protect ischemic myocardium through paracrine effects that can be further augmented with preconditioning. In in vitro experiments, cell survival factors such as Akt and eNOS were significantly increased in BMSCs following anoxia. In the second series of experiments following coronary ligation in mice, left ventricles were randomly injected with the following: DMEM (G-1), BMSCs (G-2), and preconditioned BMSCs (G-3). Four days after myocardial infarction, BMSCs were observed within injured myocardium in G-2 and G-3. Apoptotic cardiomyocytes within periinfarct area were significantly reduced in G-3. Four weeks after myocardial infarction, smaller left ventricular (LV) dimension and increased LV ejection fraction were observed in G-3. Infarct area was significantly reduced in G-3. However, GFP+ cardiomyocytes were observed in low numbers within periinfarct area in G-2 and G-3. In conclusion, BMSCs secreted cell survival factors under ischemia, and they prevented apoptosis in cardiomyocytes adjacent to the infarcted area. Preconditioning of BMSCs enhanced their survival and ability to attenuate LV remodeling, which was attributable, in part, to paracrine effects.
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              Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization.

              Endothelial precursor cells (EPCs) have been identified in adult peripheral blood. We examined whether EPCs could be isolated from umbilical cord blood, a rich source for hematopoietic progenitors, and whether in vivo transplantation of EPCs could modulate postnatal neovascularization. Numerous cell clusters, spindle-shaped and attaching (AT) cells, and cord-like structures developed from culture of cord blood mononuclear cells (MNCs). Fluorescence-trace experiments revealed that cell clusters, AT cells, and cord-like structures predominantly were derived from CD34-positive MNCs (MNC(CD34+)). AT cells and cell clusters could be generated more efficiently from cord blood MNCs than from adult peripheral blood MNCs. AT cells incorporated acetylated-LDL, released nitric oxide, and expressed KDR, VE-cadherin, CD31, and von Willebrand factor but not CD45. Locally transplanted AT cells survived and participated in capillary networks in the ischemic tissues of immunodeficient nude rats in vivo. AT cells thus had multiple endothelial phenotypes and were defined as a major population of EPCs. Furthermore, laser Doppler and immunohistochemical analyses revealed that EPC transplantation quantitatively augmented neovascularization and blood flow in the ischemic hindlimb. In conclusion, umbilical cord blood is a valuable source of EPCs, and transplantation of cord blood-derived EPCs represents a promising strategy for modulating postnatal neovascularization.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2009
                September 2009
                15 July 2009
                : 114
                : 3
                : 199-207
                Affiliations
                aDepartment of Cardiovascular Medicine, Hannover Medical School, Hannover, Germany; bCardiovascular Center, Cardiology, University Hospital Zürich, Zürich, Switzerland
                Article
                228644 Cardiology 2009;114:199–207
                10.1159/000228644
                19602881
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 2, References: 38, Pages: 9
                Categories
                Original Research

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