Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming with Cardiosphere-Derived Extracellular Membrane Vesicles

Eleni Tseliou, Joseph Fouad, Heidi Reich, Leandro Slipczuk, Geoffrey De Couto, Mark Aminzadeh, Ryan Middleton, Jackelyn Valle, Liu Weixin, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

Background Cardiosphere-derived cells mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of cardiosphere-derived cells are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMVs). Objectives This study sought to investigate the effect of cardiosphere-derived EMVs (CSp-EMVs) on fibroblasts in vitro and tested whether priming with CSp-EMVs could confer salutary properties on fibroblasts in vivo. Methods CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMVs for 24 h followed by exosomal micro-ribonucleic acid profiling. In vivo, we injected CSp-EMV-primed or -unprimed dermal fibroblasts (or CSp-EMVs) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. Results CSp-EMVs amplified their own biological signals: exposure of "inert" fibroblasts to CSp-EMVs rendered the fibroblasts therapeutic. Intramyocardially injected CSp-EMV-primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell-derived factor 1 and vascular endothelial growth factor and dramatically changed the micro-ribonucleic acid profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. Conclusions CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically active cells reveals a novel mechanism for amplification of exosome bioactivity.

Original languageEnglish (US)
Pages (from-to)599-611
Number of pages13
JournalJournal of the American College of Cardiology
Volume66
Issue number6
DOIs
StatePublished - Aug 11 2015
Externally publishedYes

Fingerprint

Fibroblasts
Membranes
Exosomes
Myocardial Infarction
Extracellular Vesicles
RNA
Chemokine CXCL12
Skin
Serum-Free Culture Media
Cardiomyopathies
Vascular Endothelial Growth Factor A
Cicatrix
Regeneration
Phenotype
Therapeutics

Keywords

  • cardiac repair
  • conversion
  • exosome
  • growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming with Cardiosphere-Derived Extracellular Membrane Vesicles. / Tseliou, Eleni; Fouad, Joseph; Reich, Heidi; Slipczuk, Leandro; De Couto, Geoffrey; Aminzadeh, Mark; Middleton, Ryan; Valle, Jackelyn; Weixin, Liu; Marbán, Eduardo.

In: Journal of the American College of Cardiology, Vol. 66, No. 6, 11.08.2015, p. 599-611.

Research output: Contribution to journalArticle

Tseliou, E, Fouad, J, Reich, H, Slipczuk, L, De Couto, G, Aminzadeh, M, Middleton, R, Valle, J, Weixin, L & Marbán, E 2015, 'Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming with Cardiosphere-Derived Extracellular Membrane Vesicles', Journal of the American College of Cardiology, vol. 66, no. 6, pp. 599-611. https://doi.org/10.1016/j.jacc.2015.05.068
Tseliou, Eleni ; Fouad, Joseph ; Reich, Heidi ; Slipczuk, Leandro ; De Couto, Geoffrey ; Aminzadeh, Mark ; Middleton, Ryan ; Valle, Jackelyn ; Weixin, Liu ; Marbán, Eduardo. / Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming with Cardiosphere-Derived Extracellular Membrane Vesicles. In: Journal of the American College of Cardiology. 2015 ; Vol. 66, No. 6. pp. 599-611.
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AU - Tseliou, Eleni

AU - Fouad, Joseph

AU - Reich, Heidi

AU - Slipczuk, Leandro

AU - De Couto, Geoffrey

AU - Aminzadeh, Mark

AU - Middleton, Ryan

AU - Valle, Jackelyn

AU - Weixin, Liu

AU - Marbán, Eduardo

PY - 2015/8/11

Y1 - 2015/8/11

N2 - Background Cardiosphere-derived cells mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of cardiosphere-derived cells are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMVs). Objectives This study sought to investigate the effect of cardiosphere-derived EMVs (CSp-EMVs) on fibroblasts in vitro and tested whether priming with CSp-EMVs could confer salutary properties on fibroblasts in vivo. Methods CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMVs for 24 h followed by exosomal micro-ribonucleic acid profiling. In vivo, we injected CSp-EMV-primed or -unprimed dermal fibroblasts (or CSp-EMVs) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. Results CSp-EMVs amplified their own biological signals: exposure of "inert" fibroblasts to CSp-EMVs rendered the fibroblasts therapeutic. Intramyocardially injected CSp-EMV-primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell-derived factor 1 and vascular endothelial growth factor and dramatically changed the micro-ribonucleic acid profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. Conclusions CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically active cells reveals a novel mechanism for amplification of exosome bioactivity.

AB - Background Cardiosphere-derived cells mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of cardiosphere-derived cells are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMVs). Objectives This study sought to investigate the effect of cardiosphere-derived EMVs (CSp-EMVs) on fibroblasts in vitro and tested whether priming with CSp-EMVs could confer salutary properties on fibroblasts in vivo. Methods CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMVs for 24 h followed by exosomal micro-ribonucleic acid profiling. In vivo, we injected CSp-EMV-primed or -unprimed dermal fibroblasts (or CSp-EMVs) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. Results CSp-EMVs amplified their own biological signals: exposure of "inert" fibroblasts to CSp-EMVs rendered the fibroblasts therapeutic. Intramyocardially injected CSp-EMV-primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell-derived factor 1 and vascular endothelial growth factor and dramatically changed the micro-ribonucleic acid profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. Conclusions CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically active cells reveals a novel mechanism for amplification of exosome bioactivity.

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