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In Vitro Differentiation of Human Mesenchymal Stem Cells into Functional Cardiomyocyte-like Cells
Published on: August 9, 2017
Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular
Joshua Mayourian1, Timothy J Cashman1, Delaine K Ceholski1
1From 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.).
Human mesenchymal stem cell (hMSC) therapy for heart failure is promising. This study reveals hMSC paracrine signaling, not cell coupling, significantly improves cardiac contractility and reduces arrhythmia risk, with exosomes playing a key role.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Biomedical Engineering
Background:
- Human mesenchymal stem cells (hMSCs) are explored for treating heart failure.
- The distinct roles of hMSC heterocellular coupling (HC) and paracrine signaling (PS) on cardiac function are not fully understood.
- Understanding these mechanisms is crucial for optimizing stem cell therapies.
Purpose of the Study:
- To elucidate the independent and combined effects of hMSC PS and HC on human cardiac contractility and arrhythmogenicity.
- To integrate experimental data with computational modeling for a comprehensive analysis.
- To identify the specific components of hMSC secretome responsible for paracrine effects.
Main Methods:
- Developed an extended computational model of hMSC-cardiomyocyte heterocellular coupling (HC).
- Incorporated experimentally validated hMSC paracrine signaling (PS) effects on cardiomyocyte calcium handling and fibrosis.
- Performed excitation-contraction simulations and validated with human engineered cardiac tissue (hECT) experiments.
- Utilized proteomic analysis to identify key signaling pathways and exosome involvement.
Main Results:
- hMSC paracrine signaling (PS) significantly increased developed force (≈4-fold) in hECTs, primarily driving contractility improvements.
- hMSC HC had minimal impact on isolated cardiomyocyte contractility, with PS being the dominant factor.
- hMSC PS protected fibrotic cardiac tissue from proarrhythmic effects associated with HC.
- Exosomes within the hMSC secretome were identified as key mediators of paracrine effects on contractility and calcium handling genes.
Conclusions:
- hMSC paracrine signaling is the primary driver of improved cardiac contractility and reduced arrhythmogenicity.
- Heterocellular coupling (HC) plays a minor role in contractility and can be counteracted by PS in fibrotic tissue.
- Exosomes are critical effectors of hMSC paracrine signaling, offering novel therapeutic insights.
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