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      • Record: found
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      Hepatocyte Growth Factor Modification Enhances the Anti-Arrhythmic Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells

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          Abstract

          Background/Aims

          Chronic myocardial infarction (MI) results in the formation of arrhythmogenic substrates, causing lethal ventricular arrhythmia (VA). We aimed to determine whether mesenchymal stem cells (MSCs) carrying a hepatocyte growth factor (HGF) gene modification (HGF-MSCs) decrease the levels of arrhythmogenic substrates and reduce the susceptibility to developing VA compared with unmodified MSCs and PBS in a swine infarction model.

          Methods

          The left descending anterior artery was balloon-occluded to establish an MI model. Four weeks later, the randomly grouped pigs were administered MSCs, PBS or HGF-MSCs via thoracotomy. After an additional four weeks, dynamic electrocardiography was performed to assess heart rate variability, and programmed electrical stimulation was conducted to evaluate the risk for VA. Then, the pigs were euthanized for morphometric, immunofluorescence and western blot analyses. Results: The HGF-MSC group displayed the highest vessel density and Cx43 expression levels, and the lowest levels of apoptosis, and tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) expression. Moreover, the HGF-MSC group exhibited a decrease in the number of sympathetic nerve fibers, substantial decreases in the low frequency and the low-/high- frequency ratio and increases in the root mean square of successive differences (rMSSD) and the percentage of successive normal sinus R-R intervals longer than 50 ms (pNN50), compared with the other two groups. Finally, the HGF-MSC group displayed the lowest susceptibility to developing VA.

          Conclusion

          HGF-MSCs displayed potent antiarrhythmic effects, reducing the risk for VA.

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          Most cited references32

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          Relationship between regional cardiac hyperinnervation and ventricular arrhythmia.

          M Fishbein, Si Chen, Xue-Jun Wu … (2000)
          Sympathetic nerve activity is known to be important in ventricular arrhythmogenesis, but there is little information on the relation between the distribution of cardiac sympathetic nerves and the occurrence of spontaneous ventricular arrhythmias in humans. We studied 53 native hearts of transplant recipients, 5 hearts obtained at autopsy of patients who died of noncardiac causes, and 7 ventricular tissues that had been surgically resected from the origin of ventricular tachycardia. The history was reviewed to determine the presence (group 1A) or absence (group 1B) of spontaneous ventricular arrhythmias. Immunocytochemical staining for S100 protein, neurofilament protein, tyrosine hydroxylase, and protein gene product 9.5 was performed to study the distribution and the density of sympathetic nerves. The average left ventricular ejection fraction was 0.22+/-0.07. A total of 30 patients had documented ventricular arrhythmias, including ventricular tachycardia and sudden cardiac death. A regional increase in sympathetic nerves was observed around the diseased myocardium and blood vessels in all 30 hearts. The density of nerve fibers as determined morphometrically was significantly higher in group 1A patients (total nerve number 19.6+/-11.2/mm(2), total nerve length 3.3+/-3.0 mm/mm(2)) than in group 1B patients (total nerve number 13.5+/-6.1/mm(2), total nerve length 2.0+/-1.1 mm/mm(2), P<0. 05 and P<0.01, respectively). There is an association between a history of spontaneous ventricular arrhythmia and an increased density of sympathetic nerves in patients with severe heart failure. These findings suggest that abnormally increased postinjury sympathetic nerve density may be in part responsible for the occurrence of ventricular arrhythmia and sudden cardiac death in these patients.
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            Autologous transplantation of bone marrow cells improves damaged heart function.

            S Tomita, R-K Li, R Weisel … (1999)
            Autologous bone marrow cells (BMCs) transplanted into ventricular scar tissue may differentiate into cardiomyocytes and restore myocardial function. This study evaluated cardiomyogenic differentiation of BMCs, their survival in myocardial scar tissue, and the effect of the implanted cells on heart function. BMCs from adult rats were cultured in cell culture medium (control) and medium with 5-azacytidine (5-aza, 10 micromol/L), TGFbeta1 (10 ng/mL), or insulin (1 nmol/L) (n=6, each group). Only BMCs cultured with 5-aza formed myotubules which stained positively for troponin I and myosin heavy chain. In vivo studies: a cryoinjury-derived scar was formed in the left ventricular free wall. At 3 weeks after injury, fresh BMCs (n=9), cultured BMCs (n=9), 5-aza-induced BMCs (n=12), and medium (control, n=12) were autologously transplanted into the scar. Heart function was measured at 8 weeks after myocardial injury. Cardiac-like muscle cells which stained positively for myosin heavy chain and troponin I were observed in the scar tissue of the 3 groups of BMC transplanted hearts. Only the 5-aza-treated BMC transplanted hearts had systolic and developed pressures which were higher (P<0.05) than that of the control hearts. All transplanted BMCs induced angiogenesis in the scar. Transplantation of BMCs induced angiogenesis. BMCs cultured with 5-aza differentiated into cardiac-like muscle cells in culture and in vivo in ventricular scar tissue and improved myocardial function.
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              The regulation of anoikis: MEKK-1 activation requires cleavage by caspases.

              G Salvesen, M Cardone, S Frisch … (1997)
              Certain cell types undergo apoptosis when they lose integrin-mediated contacts with the extracellular matrix ("anoikis"). The Jun N-terminal kinase (JNK) pathway is activated in and promotes anoikis. This activation requires caspase activity. We presently report that a DEVD motif-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix contact. This cleavage is required for the activation of the kinase activity. When overexpressed, the MEKK-1 cleavage product stimulates apoptosis; the wild-type, full-length MEKK-1 sensitizes cells to anoikis; and a cleavage-resistant mutant of MEKK-1 partially protects cells against anoikis. The cleavage-resistant or kinase-inactive mutants also prevent caspase-7 from being activated completely. Thus, caspases can induce apoptosis by activating MEKK-1, which in turn activates more caspase activity, comprising a positive feedback loop.
              Article 0 comments Cited 65 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Guo-Chang Fan: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 31 October 2014
                Volume: 9
                Issue: 10
                Electronic Location Identifier: e111246
                Affiliations
                [1 ]Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
                [2 ]Department of Cardiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
                [3 ]Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
                University of Cincinnati, College of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interest exist.

                Conceived and designed the experiments: KJC JZ. Performed the experiments: JZ LLW WD WZJ YLM YC ZDW WJG FXZ. Analyzed the data: JZ YCY. Contributed reagents/materials/analysis tools: HW CTW XRL. Wrote the paper: JZ.

                Article
                Publisher ID: PONE-D-14-33661
                DOI: 10.1371/journal.pone.0111246
                PMC ID: 4216066
                PubMed ID: 25360679
                SO-VID: 500dbeb9-a353-4a49-9d9f-46d443ff049c
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 27 July 2014
                Date accepted : 17 September 2014
                Page count
                Pages: 9
                Funding
                This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81170157, 81170160, 81470456), Six Peak Talents Foundation of Jiangsu Province (Grant No. 2011-WS-071), the Graduate Innovation Foundation of Jiangsu Province (Grant No. CXZZ 12_0568, JX22013218). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Stem Cells
                Subject: Mesenchymal Stem Cells
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Cardiac Arrest
                Subject: Cardiac Pacing
                Subject: Sudden Cardiac Death
                Subject: Clinical Genetics
                Subject: Stem Cell Therapy
                Subject: Surgical and Invasive Medical Procedures
                Subject: Blood and Lymphatic System Procedures
                Subject: Stem Cell Transplantation
                Subject: Transplantation
                Subject: Cell Transplantation
                Subject: Research and Analysis Methods
                Subject: Bioassays and Physiological Analysis
                Subject: Electrophysiological Techniques
                Subject: Cardiac Electrophysiology
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the papaer and its supporting information files.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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