title: Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury.
abstract: We have previously identified exosomes as the paracrine factor secreted by mesenchymal stem cells. Recently, we found that the key features of reperfusion injury, namely loss of ATP/NADH, increased oxidative stress and cell death were underpinned by proteomic deficiencies in ischemic/reperfused myocardium, and could be ameliorated by proteins in exosomes. To test this hypothesis in vivo, mice (C57Bl6/J) underwent 30 min ischemia, followed by reperfusion (I/R injury). Purified exosomes or saline was administered 5 min before reperfusion. Exosomes reduced infarct size by 45% compared to saline treatment. Langendorff experiments revealed that intact but not lysed exosomes enhanced viability of the ischemic/reperfused myocardium. Exosome treated animals exhibited significant preservation of left ventricular geometry and contractile performance during 28 days follow-up. Within an hour after reperfusion, exosome treatment increased levels of ATP and NADH, decreased oxidative stress, increased phosphorylated-Akt and phosphorylated-GSK-3β, and reduced phosphorylated-c-JNK in ischemic/reperfused hearts. Subsequently, both local and systemic inflammation were significantly reduced 24h after reperfusion. In conclusion, our study shows that intact exosomes restore bioenergetics, reduce oxidative stress and activate pro-survival signaling, thereby enhancing cardiac function and geometry after myocardial I/R injury. Hence, mesenchymal stem cell-derived exosomes are a potential adjuvant to reperfusion therapy for myocardial infarction.
authors: Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. f.arslan@umcutrecht.nl
authors: Fatih
authors: F
authors: Arslan
authors: Ruenn Chai
authors: RC
authors: Lai
authors: Mirjam B
authors: MB
authors: Smeets
authors: Lars
authors: L
authors: Akeroyd
authors: Andre
authors: A
authors: Choo
authors: Eissa N E
authors: EN
authors: Aguor
authors: Leo
authors: L
authors: Timmers
authors: Harold V
authors: HV
authors: van Rijen
authors: Pieter A
authors: PA
authors: Doevendans
authors: Gerard
authors: G
authors: Pasterkamp
authors: Sai Kiang
authors: SK
authors: Lim
authors: Dominique P
authors: DP
authors: de Kleijn
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3