title: Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) are bone marrow stromal cells that are in phase 1 clinical studies of cellular cardiomyoplasty. However, the electrophysiological effects of MSC transplantation have not been studied. Although improvement of ventricular function would represent a positive outcome of MSC transplantation, focal application of stem cells has the potential downside of creating inhomogeneities that may predispose the heart to reentrant arrhythmias. In the present study we use an MSC and neonatal rat ventricular myocyte (NRVM) coculture system to investigate potential proarrhythmic consequences of MSC transplantation into the heart.
  
  
  RESULTS
  Human MSCs were cocultured with NRVMs in ratios of 1:99, 1:9, and 1:4 and optically mapped. We found that conduction velocity was decreased in cocultures compared with controls, but action potential duration (APD80) was not affected. Reentrant arrhythmias were induced in 86% of cocultures containing 10% and 20% MSCs (n=36) but not in controls (n=7) or cocultures containing only 1% MSCs (n=4). Immunostaining, Western blot, and dye transfer revealed the presence of functional gap junctions involving MSCs.
  
  
  CONCLUSIONS
  Our results suggest that mixtures of MSCs and NRVMs can produce an arrhythmogenic substrate. The mechanism of reentry is probably increased tissue heterogeneity resulting from electric coupling of inexcitable MSCs with myocytes.
authors.affiliation: Division of Cardiology, Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Marvin G
authors.initials: MG
authors.lastname: Chang
authors.forename: Leslie
authors.initials: L
authors.lastname: Tung
authors.forename: Rajesh B
authors.initials: RB
authors.lastname: Sekar
authors.forename: Connie Y
authors.initials: CY
authors.lastname: Chang
authors.forename: Josh
authors.initials: J
authors.lastname: Cysyk
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.forename: M Roselle
authors.initials: MR
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology; D051381:Rats; D013997:Time Factors
chemical_list: D018031:Connexin 43