1. Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles.
- Author
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Tseliou E, Fouad J, Reich H, Slipczuk L, de Couto G, Aminzadeh M, Middleton R, Valle J, Weixin L, and Marbán E
- Subjects
- Albumins therapeutic use, Animals, Cell Membrane transplantation, Cells, Cultured, Clathrin-Coated Vesicles physiology, Clathrin-Coated Vesicles transplantation, Female, Fibroblasts transplantation, Fibrosis pathology, Fibrosis therapy, Humans, Male, Myocardial Infarction therapy, Polyesters therapeutic use, Rats, Rats, Inbred BN, Rats, Inbred WKY, Rats, Sprague-Dawley, Albumins physiology, Apoptosis physiology, Cell Membrane physiology, Fibroblasts physiology, Myocardial Infarction pathology, Neovascularization, Physiologic physiology
- 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., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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