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contributor authorزینب نشاطیen
contributor authorZeinab Neshatifa
date accessioned2020-06-06T14:24:22Z
date available2020-06-06T14:24:22Z
date copyright8/29/2015
date issued2015
identifier urihttps://libsearch.um.ac.ir:443/fum/handle/fum/3395310?locale-attribute=fa&show=full
description abstractPurpose: The technologydriven,rapid lifestyle changes over the past century exceed the evolutionary and

biological adaptability of the human heart, which renders it susceptible to degenerative diseases. Loss of

ventricular cardiomyocytes (CMCs) is inadequately compensated by electromechanically incompetent

fibroblasts. This maladaptive and proarrhythmic cellular response raised our interest in creating a new,

cardiomyocytelike cell type by forced fusion between fibroblasts and surrounding fibroblasts. We hypothesized such forced heterocellular fusion (FHF) transfers desirable electromechanical properties to fibroblasts and thereby ameliorates fibrosisassociated proarrhythmic effects on cardiac tissue.

Methods: Human ventricular scar cells (hVSCs) were isolated from myocardial scars of heart failure patients

and cocultured (1:4) with neonatal rat CMCs (nrCMCs) into confluent monolayers. Prior to coculture,

hVSCs were transduced with lentiviral vectors encoding the enhanced green fluorescent protein (eGFP, control cultures) or eGFP and the fusogenic vesicular stomatitis virus G protein (fused cultures). The structural and functional effects of FHF were investigated by (humanspecific) immunocytological staining, patchclamp and optical mapping. Results: hVSCnrCMC heterokaryons were only observed in fused (VSVG

expressing) cultures. Such heterokaryons contained 6±3 nuclei (46±18% of human origin). These new, excitable and contractile cells expressed αactinin and Cx43. Nuclear expression of NKX2.5 was absent in control hVSCs, while hVSC nuclei in heterokaryons stained positive. Expression levels of Cav1.2 and Cx43 did not relate to the percentage of human nuclei (R2=0.05), suggesting phenotypical dominance of CMCs. Additionally, FHF strongly reduced action potential duration (APD80, 313.1±6.3ms vs. 510.7±11.8ms, p<0.05 and dispersion of repolarization (75.1±4.3ms vs. 125.9±9.4ms, p<0.05). Importantly, early afterdepolarizations (EADs) rarely occurred in fused cultures (4.6% [n=65] vs. 43.4% [n=60], p<0.0001). Mechanistically, this enhanced repolarization force was due to an increased outward Kv current, as partial inhibition by tetraethylammonium chloride (TEA) reverted the antiarrhythmic

effects of fusion towards control values (7.9% to 34.2% EADs (p<0.001).Conclusions: FHF between nrCMCs and hVSCs represents a novel approach to counteract proarrhythmogeneity of hVSCs by forcing a CMClike phenotype that increases repolarization reserve. These results provide proofofconcept

for a previously unexplored therapeutic potential of heterocellular fusion.
en
languageEnglish
titleCreating new trans-species types of myocytes By forced fusion between cardiomyocytes And fibroblasts to counteract arrhythmias: Breaking boundaries with muscular mixtures.en
typeConference Paper
contenttypeExternal Fulltext
subject keywordscardiomyocytesen
subject keywordsfusionen
subject keywordsfibroblastsen
subject keywordsarrhythmiasen
identifier linkhttps://profdoc.um.ac.ir/paper-abstract-1060987.html
conference titleEuropean Society of Cardiologyen
conference locationلندنfa
identifier articleid1060987


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