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Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes.

Publication ,  Journal Article
Rogers, TB; Pati, S; Gaa, S; Riley, D; Khakoo, AY; Patel, S; Wardlow, RD; Frederick, CA; Hall, G; He, L-P; Lederer, WJ
Published in: J Mol Cell Cardiol
February 2011

Since massive irreversible loss of cardiac myocytes occurs following myocardial injury, injection of human mesenchymal stem cells (hMSCs) has emerged as a promising therapeutic intervention. Despite the growing enthusiasm for this approach, the understanding of how hMSCs evoke cardiac improvement is ever more controversial. The present study critically tests hypothesis that hMSCs provide specific benefit directly to damaged ventricular myocytes. Cultures of neonatal mouse ventricular cardiac myocytes (nMCM) were subjected to two distinct acute stress protocols; incubations with either endotoxin, lipopolysaccharide (LPS) or toxic cytokine, IL-1β. Myocyte injury was assessed in intracellular Ca(2+) signaling assays in fluo-3-loaded nMCMs that were imaged with high temporal resolution by fluorescent microscopy. Following LPS or IL-1β treatment there was profound myocyte injury, manifest by chaotic [Ca(2+)](i) handling, quantified as a 3- to 5-fold increase in spontaneous [Ca(2+)](i) transients. Antibody neutralization experiments reveal such damage is mediated in part by interleukin-18 and not by tumor necrosis factor-α (TNF-α). Importantly, normal [Ca(2+)](i) signaling was preserved when cardiomyocytes were co-cultured with hMSCs. Since normal [Ca(2+)](i) handling was maintained in transwell cultures, where nMCMs and hMSCs were separated by a permeable membrane, a protective paracrine signaling cascade is operable. hMSCs provoke a genetic reprogramming of cardiomyocytes. LPS provokes release of TNFα from nMCMs which is blocked by hMSCs grown in co- or transwell cultures. Consistent with cytokine release, flow cytometry analyses reveal that hMSCs also block the LPS- and IL-1β-dependent activation of cardiac transcription factor, NF-κB. Importantly, hMSC-conditioned medium restores normal Ca(2+) signaling in LPS- and IL-1β-damaged nMCMs. These results reveal new evidence that hMSCs elicit protective and reparative effects on cardiac tissue through molecular reprogramming of the cardiac myocytes themselves. Thus these studies provide novel new insight into the cellular and molecular mechanisms that underlie the therapeutic benefit of hMSCs in the setting of heart failure. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".

Duke Scholars

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

February 2011

Volume

50

Issue

2

Start / End Page

346 / 356

Location

England

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Signal Transduction
  • Paracrine Communication
  • NF-kappa B
  • Myocytes, Cardiac
  • Models, Biological
  • Mice
  • Mesenchymal Stem Cells
  • Lipopolysaccharides
  • Interleukin-1beta
 

Citation

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Rogers, T. B., Pati, S., Gaa, S., Riley, D., Khakoo, A. Y., Patel, S., … Lederer, W. J. (2011). Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes. J Mol Cell Cardiol, 50(2), 346–356. https://doi.org/10.1016/j.yjmcc.2010.09.001
Rogers, Terry B., Shibani Pati, Shirley Gaa, Dushon Riley, Aarif Y. Khakoo, Shalin Patel, Robert D. Wardlow, et al. “Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes.J Mol Cell Cardiol 50, no. 2 (February 2011): 346–56. https://doi.org/10.1016/j.yjmcc.2010.09.001.
Rogers TB, Pati S, Gaa S, Riley D, Khakoo AY, Patel S, et al. Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes. J Mol Cell Cardiol. 2011 Feb;50(2):346–56.
Rogers, Terry B., et al. “Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes.J Mol Cell Cardiol, vol. 50, no. 2, Feb. 2011, pp. 346–56. Pubmed, doi:10.1016/j.yjmcc.2010.09.001.
Rogers TB, Pati S, Gaa S, Riley D, Khakoo AY, Patel S, Wardlow RD, Frederick CA, Hall G, He L-P, Lederer WJ. Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes. J Mol Cell Cardiol. 2011 Feb;50(2):346–356.
Journal cover image

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

February 2011

Volume

50

Issue

2

Start / End Page

346 / 356

Location

England

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Signal Transduction
  • Paracrine Communication
  • NF-kappa B
  • Myocytes, Cardiac
  • Models, Biological
  • Mice
  • Mesenchymal Stem Cells
  • Lipopolysaccharides
  • Interleukin-1beta