Copyright © 2006, European Society of Cardiology
Progressive increase in conduction velocity across human mesenchymal stem cells is mediated by enhanced electrical coupling
aDepartment of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
bMolecular Cell Biology, Section Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author. Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 715262020; fax: +31 715266809. Email address: D.E.Atsma{at}lumc.nl
Objective: The purpose of the study was to investigate the development of electrical transmission across human adult bone marrow-derived mesenchymal stem cells (hMSCs) during long-term co-incubation with cardiomyocytes (CMCs).
Methods: Neonatal rat CMCs were cultured in multi-electrode array dishes. A conduction block was induced by creating a central acellular channel, yielding two asynchronously beating CMC fields. Enhanced green fluorescent protein (eGFP)-labeled hMSCs from ischemic heart disease patients (n=8), eGFP-labeled hMSCs having RNA interference-mediated connexin43 (Cx43) knockdown (n=6), 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (Dil)-labeled CMCs (n=6), or no cells (n=9) were seeded in the channel. Assessment of conduction velocity (CV), Cx expression and localization, gap junctional coupling, and intracellular electrical recordings were performed for up to 14 days.
Results: Resynchronization of the two CMC fields occurred within 24 h after seeding of hMSCs. CV across hMSCs increased from 1.4±0.4 cm/s at day 7 to 3.5±0.1 cm/s (p<0.05) at day 14. CV across seeded CMCs was 16.8±0.2 cm/s throughout this period. No resynchronization occurred in the absence of seeded cells. Knockdown of Cx43 in hMSCs abolished conduction across the channel completely. Time-dependent increase of CV across hMSCs was associated with increased Cx43 mRNA and protein expression resulting in increased gap junctional coupling. Intracellular recordings in coupled hMSCs showed increased conducted action potential (AP) amplitude, lower resting membrane potential, and decreased duration of conducted AP (p<0.05, day 14 versus day 1).
Conclusions: CV across hMSCs increases progressively after 7 days of co-incubation with CMCs, most likely via improved electrotonic interaction. This is associated with increased Cx43 expression, increased functional gap junctional coupling, and enhanced intercellular electrical coupling between hMSCs and CMCs.
KEYWORDS Stem cells; Conduction; Conduction block; Gap junctions; Connexins; Myocytes
Time for primary review 22 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Macia and P. A. Boyden Stem Cell Therapy Is Proarrhythmic Circulation, April 7, 2009; 119(13): 1814 - 1823. [Full Text] [PDF]
|
|
|
|
 |
|
 J van Ramshorst, D E Atsma, S L M A Beeres, S A Mollema, N Ajmone Marsan, E R Holman, E E van der Wall, M J Schalij, and J J Bax Effect of intramyocardial bone marrow cell injection on left ventricular dyssynchrony and global strain Heart, January 15, 2009; 95(2): 119 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Lau, C. Clausen, E. A. Sosunov, I. N. Shlapakova, E. P. Anyukhovsky, P. Danilo Jr, T. S. Rosen, C. Kelly, H. S. Duffy, M. J. Szabolcs, et al. Epicardial Border Zone Overexpression of Skeletal Muscle Sodium Channel SkM1 Normalizes Activation, Preserves Conduction, and Suppresses Ventricular Arrhythmia: An In Silico, In Vivo, In Vitro Study Circulation, January 6, 2009; 119(1): 19 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Pijnappels, M. J. Schalij, and D. E. Atsma Response to the Letter by Rose et al Circ. Res., January 2, 2009; 104(1): e8 - e8. [Full Text] [PDF]
|
|
|
|
|
|
D. A. Pijnappels, M. J. Schalij, A. A. Ramkisoensing, J. van Tuyn, A. A.F. de Vries, A. van der Laarse, D. L. Ypey, and D. E. Atsma Forced Alignment of Mesenchymal Stem Cells Undergoing Cardiomyogenic Differentiation Affects Functional Integration With Cardiomyocyte Cultures Circ. Res., July 18, 2008; 103(2): 167 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Pedrotty, R. Y. Klinger, N. Badie, S. Hinds, A. Kardashian, and N. Bursac Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H390 - H400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Pijnappels, J. van Tuyn, A. A.F. de Vries, R. W. Grauss, A. van der Laarse, D. L. Ypey, D. E. Atsma, and M. J. Schalij Resynchronization of Separated Rat Cardiomyocyte Fields With Genetically Modified Human Ventricular Scar Fibroblasts Circulation, October 30, 2007; 116(18): 2018 - 2028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. van Tuyn, D. A. Pijnappels, A. A. F. de Vries, I. de Vries, I. van der Velde-van Dijke, S. Knaan-Shanzer, A. van der Laarse, M. J. Schalij, and D. E. Atsma Fibroblasts from human postmyocardial infarction scars acquire properties of cardiomyocytes after transduction with a recombinant myocardin gene FASEB J, October 1, 2007; 21(12): 3369 - 3379. [Abstract] [Full Text] [PDF]
|
|