title: Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles.
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).
  
  
  OBJECTIVE
  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.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tseliou
authors.affiliation: Harvard College, Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fouad
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Heidi
authors.initials: H
authors.lastname: Reich
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Leandro
authors.initials: L
authors.lastname: Slipczuk
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: de Couto
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Aminzadeh
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Ryan
authors.initials: R
authors.lastname: Middleton
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Jackelyn
authors.initials: J
authors.lastname: Valle
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Liu
authors.initials: L
authors.lastname: Weixin
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California. Electronic address: Eduardo.Marban@csmc.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000418:Albumins / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology* / Q000637:transplantation; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000502:physiology / Q000637:transplantation; D005260:Female; D005347:Fibroblasts / Q000502:physiology* / Q000637:transplantation; D005355:Fibrosis / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011091:Polyesters / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley
chemical_list: D000418:Albumins; C522044:PB-127 compound; D011091:Polyesters
keywords: cardiac repair; conversion; exosome; growth factor