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

doi: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

Journal article

Open access

Peer reviewed

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, …

Circulation research, Vol.121(4), pp.411-423

2017-08-04

DOI: https://doi.org/10.1161/CIRCRESAHA.117.310796

PMCID: PMC5899516

PMID: 28642329

Abstract

Excitation Contraction Coupling - physiology

Humans

Myocardial Contraction - physiology

Cells, Cultured

Mesenchymal Stem Cells - physiology

Rats

Arrhythmias, Cardiac - physiopathology

Action Potentials - physiology

Paracrine Communication - physiology

Animals

Myocytes, Cardiac - physiology

Computer Simulation

Mice

Cell Culture Techniques

Cell Differentiation - physiology

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. The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase 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 that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ≈4-fold compared with non-hMSC-supplemented controls during physiological 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 proarrhythmic 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 exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium-handling genes (eg, SERCA2a, L-type calcium channel). 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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.102 Stem Cell Research; 1.102.110 Mesenchymal Stem Cells
Web Of Science research areas: Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease
ESI research areas: Clinical Medicine

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Title: Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity
Creators: Joshua Mayourian - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Timothy J Cashman - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Delaine K Ceholski - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Bryce V Johnson - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
David Sachs - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Deepak A Kaji - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Susmita Sahoo - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Joshua M Hare - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Roger J Hajjar - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Eric A Sobie - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.)
Kevin D Costa - From the Cardiovascular Research Center (J.M., T.J.C., D.K.C., D.S., S.S., R.J.H., K.D.C.), Department of Developmental and Regenerative Biology (D.A.K.), and Department of Pharmacology and Systems Therapeutics (E.A.S.), Icahn School of Medicine at Mount Sinai, New York; Department of Medicine, University of Washington Seattle (B.V.J.); and The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL (J.M.H.). kevin.costa@mssm.edu
Publication Details: Circulation research, Vol.121(4), pp.411-423
Publisher: United States
Grant note: T32 GM062754 / NIGMS NIH HHS R01 HL110737 / NHLBI NIH HHS R01 HL132226 / NHLBI NIH HHS HHSN268201000045C / NHLBI NIH HHS F30 HL118923 / NHLBI NIH HHS R01 HL135093 / NHLBI NIH HHS R13 AG035494 / NIA NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Interdisciplinary Stem Cell Institute
Language: English
Resource Type: Journal article
PMID: 28642329
PMCID: PMC5899516
Record Identifier: 991031560453402976