Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility

Joshua Mayourian, Delaine K. Ceholski, Przemek A. Gorski, Prabhu Mathiyalagan, Jack F. Murphy, Sophia I. Salazar, Francesca Stillitano, Joshua M. Hare, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Rationale: The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. Objective: This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies. Methods and Results: Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes. Conclusions: miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.

Original languageEnglish (US)
Pages (from-to)933-944
Number of pages12
JournalCirculation Research
Volume122
Issue number7
DOIs
StatePublished - Mar 30 2018

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MicroRNAs
Mesenchymal Stromal Cells
Calcium
Exosomes
Phosphatidylinositol 3-Kinases
Gene Expression
Stem Cells
L-Type Calcium Channels
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Systems Biology
Conditioned Culture Medium
Least-Squares Analysis
Cardiac Myocytes
Heart Diseases
Western Blotting
Regression Analysis
Technology

Keywords

  • exosomes
  • microRNAs
  • myocardium
  • systems biology
  • tissue engineering

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mayourian, J., Ceholski, D. K., Gorski, P. A., Mathiyalagan, P., Murphy, J. F., Salazar, S. I., ... Costa, K. D. (2018). Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. Circulation Research, 122(7), 933-944. https://doi.org/10.1161/CIRCRESAHA.118.312420

Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. / Mayourian, Joshua; Ceholski, Delaine K.; Gorski, Przemek A.; Mathiyalagan, Prabhu; Murphy, Jack F.; Salazar, Sophia I.; Stillitano, Francesca; Hare, Joshua M.; Sahoo, Susmita; Hajjar, Roger J.; Costa, Kevin D.

In: Circulation Research, Vol. 122, No. 7, 30.03.2018, p. 933-944.

Research output: Contribution to journalArticle

Mayourian, J, Ceholski, DK, Gorski, PA, Mathiyalagan, P, Murphy, JF, Salazar, SI, Stillitano, F, Hare, JM, Sahoo, S, Hajjar, RJ & Costa, KD 2018, 'Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility', Circulation Research, vol. 122, no. 7, pp. 933-944. https://doi.org/10.1161/CIRCRESAHA.118.312420
Mayourian, Joshua ; Ceholski, Delaine K. ; Gorski, Przemek A. ; Mathiyalagan, Prabhu ; Murphy, Jack F. ; Salazar, Sophia I. ; Stillitano, Francesca ; Hare, Joshua M. ; Sahoo, Susmita ; Hajjar, Roger J. ; Costa, Kevin D. / Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. In: Circulation Research. 2018 ; Vol. 122, No. 7. pp. 933-944.
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AU - Mayourian, Joshua

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AU - Gorski, Przemek A.

AU - Mathiyalagan, Prabhu

AU - Murphy, Jack F.

AU - Salazar, Sophia I.

AU - Stillitano, Francesca

AU - Hare, Joshua M.

AU - Sahoo, Susmita

AU - Hajjar, Roger J.

AU - Costa, Kevin D.

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N2 - Rationale: The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. Objective: This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies. Methods and Results: Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes. Conclusions: miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.

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KW - exosomes

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