title: Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction.
abstract: Background and Objective. Exosomes secreted from mesenchymal stem cells (MSC) have demonstrated cardioprotective effects. This study examined the role of exosomes derived from MSC overexpressing CXCR4 for recovery of cardiac functions after myocardial infarction (MI). Methods. In vitro, exosomes from MSC transduced with lentiviral CXCR4 (Exo(CR4)) encoding a silencing sequence or null vector were isolated and characterized by transmission electron microscopy and dynamic light scattering. Gene expression was then analyzed by qPCR and Western blotting. Cytoprotective effects on cardiomyocytes were evaluated and effects of exosomes on angiogenesis analyzed. In vivo, an exosome-pretreated MSC-sheet was implanted into a region of scarred myocardium in a rat MI model. Angiogenesis, infarct size, and cardiac functions were then analyzed. Results. In vitro, Exo(CR4) significantly upregulated IGF-1α and pAkt levels and downregulated active caspase 3 level in cardiomyocytes. Exo(CR4) also enhanced VEGF expression and vessel formation. However, effects of Exo(CR4) were abolished by an Akt inhibitor or CXCR4 knockdown. In vivo, Exo(CR4) treated MSC-sheet implantation promoted cardiac functional restoration by increasing angiogenesis, reducing infarct size, and improving cardiac remodeling. Conclusions. This study reveals a novel role of exosomes derived from MSC(CR4) and highlights a new mechanism of intercellular mediation of stem cells for MI treatment.
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA ; Department of Cardiology, The People's Hospital of Sanya, Sanya, Hainan 572000, China.
authors.forename: Ruilian
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Paul
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urinary Surgery, Xining City Hospital, Qinghai 810000, China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Meifeng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Millard
authors.affiliation: Infection Hospital of Nanchang University, Nanchang, Jiangxi 330002, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang