Mesenchymal stem cells improve cardiac conduction by upregulation of connexin 43 through paracrine signaling

Am J Physiol Heart Circ Physiol. 2013 Feb 15;304(4):H600-9. doi: 10.1152/ajpheart.00533.2012. Epub 2012 Dec 15.


Mesenchymal stem cells (MSCs) were shown to improve cell survival and alleviate cardiac arrhythmias when transplanted into cardiac tissue; however, little is known about the mechanism by which MSCs modify the electrophysiological properties of cardiac tissue. We aimed to distinguish the influence of cell-cell coupling between myocytes and MSCs from that of MSC-derived paracrine factors on the spontaneous activity and conduction velocity (θ) of multicellular cardiomyocyte preparations. HL-1 cells were plated on microelectrode arrays and their spontaneous activity and θ was determined from field potential recordings. In heterocellular cultures of MSCs and HL-1 cells the beating frequency was attenuated (t(0h): 2.26 ± 0.18 Hz; t(4h): 1.98 ± 0.26 Hz; P < 0.01) concomitant to the intercellular coupling between MSCs and cardiomyocytes. In HL-1 monolayers supplemented with MSC conditioned media (ConM) or tyrode (ConT) θ significantly increased in a time-dependent manner (ConT: t(0h): 2.4 cm/s ± 0.2; t(4h): 3.1 ± 0.4 cm/s), whereas the beating frequency remained constant. Connexin (Cx)43 mRNA and protein expression levels also increased after ConM or ConT treatment over the same time period. Enhanced low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation after ConT treatment implicates the Wnt signaling pathway. Suppression of Wnt secretion from MSCs (IWP-2; 5 μmol/l) reduced the efficacy of ConT to induce phospho-LRP6 and to increase θ. Inhibition of β-catenin (cardamonin; 10 μmol/l) or GSK3-α/β (LiCl; 5 mmol/l) also suppressed changes in θ, further supporting the hypothesis that MSC-mediated Cx43 upregulation occurs in part through secreted Wnt ligands and activation of the canonical Wnt signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Chalcones / pharmacology
  • Connexin 43 / biosynthesis*
  • Culture Media, Conditioned
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Heart Conduction System / drug effects
  • Heart Conduction System / enzymology
  • Heart Conduction System / physiology*
  • Lithium Chloride / pharmacology
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Mesenchymal Stem Cell Transplantation*
  • Mice
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / physiology
  • Paracrine Communication / drug effects
  • Paracrine Communication / physiology*
  • Phosphorylation
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / antagonists & inhibitors


  • CTNNB1 protein, mouse
  • Chalcones
  • Connexin 43
  • Culture Media, Conditioned
  • Enzyme Inhibitors
  • GJA1 protein, mouse
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp6 protein, mouse
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha
  • Lithium Chloride
  • cardamonin