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

被引:132
作者
Tseliou, Eleni [1 ]
Fouad, Joseph [2 ]
Reich, Heidi [1 ]
Slipczuk, Leandro [1 ]
de Couto, Geoffrey [1 ]
Aminzadeh, Mark [1 ]
Middleton, Ryan [1 ]
Valle, Jackelyn [1 ]
Liu Weixin [1 ]
Marban, Eduardo [1 ]
机构
[1] Cedars Sinai Heart Inst, Los Angeles, CA 90048 USA
[2] Harvard Univ, Boston, MA USA
关键词
cardiac repair; conversion; exosome; growth factor; STEM-CELLS; MYOCARDIAL-INFARCTION; CARDIAC-FUNCTION; EXOSOMES; CARDIOMYOCYTES; REGENERATION; MICRORNAS; MEDIATE; ROLES; HEART;
D O I
10.1016/j.jacc.2015.05.068
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (C) 2015 by the American College of Cardiology Foundation.
引用
收藏
页码:599 / 611
页数:13
相关论文
共 41 条
[1]   Induced regeneration-the progress and promise of direct reprogramming for heart repair [J].
Addis, Russell C. ;
Epstein, Jonathan A. .
NATURE MEDICINE, 2013, 19 (07) :829-836
[2]   Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes [J].
Alvarez-Erviti, Lydia ;
Seow, Yiqi ;
Yin, HaiFang ;
Betts, Corinne ;
Lakhal, Samira ;
Wood, Matthew J. A. .
NATURE BIOTECHNOLOGY, 2011, 29 (04) :341-U179
[3]   Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy [J].
Aminzadeh, Mohammad A. ;
Tseliou, Eleni ;
Sun, Baiming ;
Cheng, Ke ;
Malliaras, Konstantinos ;
Makkar, Raj R. ;
Marban, Eduardo .
EUROPEAN HEART JOURNAL, 2015, 36 (12) :751-762
[4]   Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy [J].
Bang, Claudia ;
Batkai, Sandor ;
Dangwal, Seema ;
Gupta, Shashi Kumar ;
Foinquinos, Ariana ;
Holzmann, Angelika ;
Just, Annette ;
Remke, Janet ;
Zimmer, Karina ;
Zeug, Andre ;
Ponimaskin, Evgeni ;
Schmiedl, Andreas ;
Yin, Xiaoke ;
Mayr, Manuel ;
Halder, Rashi ;
Fischer, Andre ;
Engelhardt, Stefan ;
Wei, Yuanyuan ;
Schober, Andreas ;
Fiedler, Jan ;
Thum, Thomas .
JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (05) :2136-2146
[5]   Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction [J].
Barile, Lucio ;
Lionetti, Vincenzo ;
Cervio, Elisabetta ;
Matteucci, Marco ;
Gherghiceanu, Mihaela ;
Popescu, Laurentiu M. ;
Torre, Tiziano ;
Siclari, Francesco ;
Moccetti, Tiziano ;
Vassalli, Giuseppe .
CARDIOVASCULAR RESEARCH, 2014, 103 (04) :530-541
[6]   Production of De Novo Cardiomyocytes: Human Pluripotent Stem Cell Differentiation and Direct Reprogramming [J].
Burridge, Paul W. ;
Keller, Gordon ;
Gold, Joseph D. ;
Wu, Joseph C. .
CELL STEM CELL, 2012, 10 (01) :16-28
[7]   TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing [J].
Chendrimada, TP ;
Gregory, RI ;
Kumaraswamy, E ;
Norman, J ;
Cooch, N ;
Nishikura, K ;
Shiekhattar, R .
NATURE, 2005, 436 (7051) :740-744
[8]   Relative Roles of Direct Regeneration Versus Paracrine Effects of Human Cardiosphere-Derived Cells Transplanted Into Infarcted Mice [J].
Chimenti, Isotta ;
Smith, Rachel Ruckdeschel ;
Li, Tao-Sheng ;
Gerstenblith, Gary ;
Messina, Elisa ;
Giacomello, Alessandro ;
Marban, Eduardo .
CIRCULATION RESEARCH, 2010, 106 (05) :971-U304
[9]   Shedding microvesicles: artefacts no more [J].
Cocucci, Emanuele ;
Racchetti, Gabriella ;
Meldolesi, Jacopo .
TRENDS IN CELL BIOLOGY, 2009, 19 (02) :43-51
[10]   Extracellular vesicles: biology and emerging therapeutic opportunities [J].
EL Andaloussi, Samir ;
Maeger, Imre ;
Breakefield, Xandra O. ;
Wood, Matthew J. A. .
NATURE REVIEWS DRUG DISCOVERY, 2013, 12 (05) :348-358