In vitro and in vivo characteristics of connexin 43-modified human skeletal myoblasts as candidates for prospective stem cell therapy for the failing heart

Abstract Background Previously, connexin 43-modified skeletal myoblasts (MbCx) were shown to reduce the pro-arrhythmic effect during the regeneration of heart tissue in an animal model of infarction. To increase the relevance to clinical implementation, in this study, we introduced connexin 43 into...

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Bibliographic Details
Published in:International journal of cardiology 2014-04, Vol.173 (1), p.55-64
Main Authors: Kolanowski, T.J, Rozwadowska, N, Malcher, A, Szymczyk, E, Kasprzak, J.D, Mietkiewski, T, Kurpisz, M
Format: Article
Language:English
Subjects:
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Applied cell therapy and gene therapy
Biological and medical sciences
Cardiology. Vascular system
Cardiovascular
Cell therapy
Cells, Cultured
Connexin 43
Connexin 43 - biosynthesis
Coronary heart disease
Genetic modification
Heart
Heart Failure - metabolism
Heart Failure - pathology
Heart Failure - therapy
Heart failure, cardiogenic pulmonary edema, cardiac enlargement
Human skeletal myoblasts
Humans
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Myoblasts, Skeletal - metabolism
Myoblasts, Skeletal - transplantation
Myocardial Infarction - metabolism
Myocardial Infarction - pathology
Myocardial Infarction - therapy
Post-infarction model
Prospective Studies
Stem Cell Transplantation - methods
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
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Summary:Abstract Background Previously, connexin 43-modified skeletal myoblasts (MbCx) were shown to reduce the pro-arrhythmic effect during the regeneration of heart tissue in an animal model of infarction. To increase the relevance to clinical implementation, in this study, we introduced connexin 43 into human myoblasts using a highly safe non-viral vector and demonstrated that their transplantation had a positive effect on the function of the injured heart. Methods and results Myoblasts were efficiently transfected with a pCiNeo-GJA1 plasmid (65.72%). qPCR analysis revealed over 32-fold higher expression of the connexin 43 gene in the MbCx cell population compared to ‘native’ controls. The susceptibility of the myoblasts to oxidative stress conditions (p < 0.001) and the fusion index (p < 0.01) were increased in the MbCx cells. Additionally, we observed changes in the MYOG and MYH2 gene expression levels in the GJA1 -modified myoblasts. Finally, we observed a significant improvement in the post-infarction echocardiographic parameters after intervention using MbCx cells compared with non-transfected myoblasts (MbWt) and the control (0.9% NaCl), wherein a significant decrease in the left ventricular area change in the short axis (SAX AC%) was observed at the two-month follow-up (p < 0.05 and p < 0.01, respectively). Conclusions We demonstrated the positive effect of connexin 43 overexpression on the biology and function of human skeletal myoblasts in the context of their potential clinical applications. Our preclinical studies using a mouse infarction model indicated the positive effect of MbCx implantation on the function of the injured heart.
ISSN:0167-5273
1874-1754
DOI:10.1016/j.ijcard.2014.02.009