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Original Research

Experimental and Computational Insight into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Joshua Mayourian, Timothy J Cashman, Delaine K Ceholski, Bryce V Johnson, David Sachs, Deepak A Kaji, Susmita Sahoo, Joshua M Hare, Roger J Hajjar, Eric A Sobie, Kevin D Costa
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https://doi.org/10.1161/CIRCRESAHA.117.310796
Circulation Research. 2017;CIRCRESAHA.117.310796
Originally published June 22, 2017
Joshua Mayourian
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Timothy J Cashman
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Delaine K Ceholski
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Bryce V Johnson
Medicine, University of Washington, Seattle
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David Sachs
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Deepak A Kaji
Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai
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Susmita Sahoo
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Joshua M Hare
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine
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Roger J Hajjar
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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Eric A Sobie
Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai
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Kevin D Costa
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
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  • For correspondence: kevin.costa@mssm.edu
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Abstract

Rationale: Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved.

Objective: To better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches.

Methods and Results: Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/SERCA activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased approximately 4-fold compared to non-hMSC-supplemented controls during physiologic 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential pro-arrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosomes-enriched, but not exosomes-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT developed force and expression of calcium handling genes (e.g., SERCA2a, L-type calcium channel).

Conclusions: Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.

  • cell therapy
  • computational biology
  • exosomes
  • electrophysiology
  • contractility
  • excitation-contraction coupling
  • Received February 9, 2017.
  • Revision received June 20, 2017.
  • Accepted June 22, 2017.

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    Experimental and Computational Insight into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity
    Joshua Mayourian, Timothy J Cashman, Delaine K Ceholski, Bryce V Johnson, David Sachs, Deepak A Kaji, Susmita Sahoo, Joshua M Hare, Roger J Hajjar, Eric A Sobie and Kevin D Costa
    Circulation Research. 2017;CIRCRESAHA.117.310796, originally published June 22, 2017
    https://doi.org/10.1161/CIRCRESAHA.117.310796

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    Experimental and Computational Insight into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity
    Joshua Mayourian, Timothy J Cashman, Delaine K Ceholski, Bryce V Johnson, David Sachs, Deepak A Kaji, Susmita Sahoo, Joshua M Hare, Roger J Hajjar, Eric A Sobie and Kevin D Costa
    Circulation Research. 2017;CIRCRESAHA.117.310796, originally published June 22, 2017
    https://doi.org/10.1161/CIRCRESAHA.117.310796
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    • Electrophysiology
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    • Contractile Function
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    • Calcium Cycling/Excitation-Contraction Coupling

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