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Extracellular Vesicles Derived from Hypoxic Human Mesenchymal Stem Cells Attenuate GSK3β Expression via miRNA-26a in an Ischemia-Reperfusion Injury Model

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초록

Purpose: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotectiveeffects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effectsof EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs). Materials and Methods: EV solutions (0.4 μg/μL) derived from normoxia-preconditioned MSCs (EVNM) and hypoxia-preconditionedMSCs (EVHM) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26staining in hearts from EV-treated rats. Results: EVHM significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electricalconduction, INa current, and Cx43 expression. EVHM also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3βinduced after IR injury. miRNA-26a was significantly increased in EVHM, compared with EVNM, in real-time PCR. Finally, in in vitroexperiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a. Conclusion: EVHM reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. Thesefindings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.

Abstract

Purpose: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotectiveeffects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effectsof EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs). Materials and Methods: EV solutions (0.4 μg/μL) derived from normoxia-preconditioned MSCs (EVNM) and hypoxia-preconditionedMSCs (EVHM) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26staining in hearts from EV-treated rats. Results: EVHM significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electricalconduction, INa current, and Cx43 expression. EVHM also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3βinduced after IR injury. miRNA-26a was significantly increased in EVHM, compared with EVNM, in real-time PCR. Finally, in in vitroexperiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a. Conclusion: EVHM reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. Thesefindings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.

참고문헌 (40)

  1. Maroko PR, "Factors influencing infarct size following experimental coronary artery occlusions", Circulation, 43, pp.67~82 (1971)[DOI]
  2. Reimer KA, "The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs", Circulation, 56, pp.786~794 (1977)[DOI]
  3. Bolli R, "Myocardial protection at a crossroads: the need for translation into clinical therapy", Circ Res, 95, pp.125~134 (2004)[DOI]
  4. Mathivanan S, "Exosomes: extracellular organelles important in intercellular communication", J Proteomics, 73, pp.1907~1920 (2010)[DOI]
  5. Yellon DM, "Exosomes: nanoparticles involved in cardioprotection?", Circ Res, 114, pp.325~332 (2014)[DOI]
  6. Raposo G, "Extracellular vesicles: exosomes, microvesicles, and friends", J Cell Biol, 200, pp.373~383 (2013)[DOI]
  7. Ratajczak J, "Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery", Leukemia, 20, pp.847~856 (2006)[DOI]
  8. Hunter MP, "Detection of microRNA expression in human peripheral blood microvesicles", PLoS One, 3, pp.e3694~ (2008)[DOI]
  9. Aliotta JM, "Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription", Exp Hematol, 38, pp.233~245 (2010)[DOI]
  10. Sahoo S, "Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity", Circ Res, 109, pp.724~728 (2011)[DOI]
  11. Lai RC, "Exosome secreted by MSC reduces myocardial ischemia", reperfusion injury, 2010, pp.4, 214~222
  12. 최문환, "Therapeutic Use of Stem Cell Transplantation for Cell Replacement or Cytoprotective Effect of Microvesicle Released from Mesenchymal Stem Cell", Molecules and Cells, 37(2), pp.133~139 (2014), 한국분자세포생물학회[DOI]
  13. Beninson LA, "Exosomes: an emerging factor in stressinduced immunomodulation", Semin Immunol, 26, pp.394~401 (2014)[DOI]
  14. Baixauli F, "Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness", Front Immunol, 5, pp.403~ (2014)
  15. Gnecchi M, "Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells", Nat Med, 11, pp.367~368 (2005)[DOI]
  16. Takahashi M, "Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury", Am J Physiol Heart Circ Physiol, 291, pp.H886~H893 (2006)[DOI]
  17. Arslan F, "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, Stem Cell Res, pp.2013, 10[DOI]
  18. Park H, "RAGE siRNA-mediated gene silencing provides cardioprotection against ventricular arrhythmias in acute ischemia and reperfusion", J Control Release, 217, pp.315~326 (2015)[DOI]
  19. Zhang J, "MicroRNA-26a promotes cholangiocarcinoma growth by activating <TEX>${\beta}$<", TEX>-catenin, 2012, pp.143, 246~256
  20. Ai Z, "Wnt-1 regulation of connexin43 in cardiac myocytes", J Clin Invest, 105, pp.161~171 (2000)[DOI]
  21. Tong H, "Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective", Circ Res, 90, pp.377~379 (2002)[DOI]
  22. Barandon L, "Involvement of FrzA", sFRP-1 and the Wnt, Circ Res, pp.2005, 96[DOI]
  23. Tong H, "Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C", Circ Res, 87, pp.309~315 (2000)[DOI]
  24. Gardner PI, "Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts", Circulation, 72, pp.596~611 (1985)[DOI]
  25. Nattel S, "Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation", Physiol Rev, 87, pp.425~456 (2007)[DOI]
  26. Lue WM, "Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current", Circulation, 85, pp.1175~1188 (1992)[DOI]
  27. Pu J, "A possible ionic mechanism for reduced excitability and postrepolarization refractoriness", Circ Res, 81, pp.110~119 (1997)[DOI]
  28. Matsushita T, "Ischaemia-induced temporal expression of connexin43 in rat heart", Virchows Arch, 431, pp.453~458 (1997)[DOI]
  29. van der Vlist EJ, "Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry", Nat Protoc, 7, pp.1311~1326 (2012)[DOI]
  30. Martinez MC, "Microparticles: targets and tools in cardiovascular disease", Trends Pharmacol Sci, 32, pp.659~665 (2011)[DOI]
  31. Wen Z, "Bone marrow mesenchymal stem cells for post-myocardial infarction cardiac repair: microRNAs as novel regulators", J Cell Mol Med, 16, pp.657~671 (2012)[DOI]
  32. Chen TS, "Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs", Nucleic Acids Res, 38, pp.215~224 (2010)[DOI]
  33. De Celle T, "Alterations in mouse cardiac proteome after in vivo myocardial infarction: permanent ischaemia versus ischaemia-reperfusion", Exp Physiol, 90, pp.593~606 (2005)[DOI]
  34. Wang X, "MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia", reperfusion-induced cardiac injury, 2010, pp.122, 1308~1318
  35. Icli B, "MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP", SMAD1 signaling, 2013, pp.113, 1231~1241
  36. Juhaszova M, "Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore", J Clin Invest, 113, pp.1535~1549 (2004)[DOI]
  37. Fukumoto S, "Akt participation in the Wnt signaling pathway through Dishevelled", J Biol Chem, 276, pp.17479~17483 (2001)[DOI]
  38. Yadav HN, "Involvement of <TEX>$GSK-3{\beta}$<", TEX> in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart, 2010, pp.343, 75~81
  39. Suh JH, "Up-regulation of miR-26a promotes apoptosis of hypoxic rat neonatal cardiomyocytes by repressing <TEX>$GSK-3{\beta}$<", TEX> protein expression, 2012, pp.423, 404~410
  40. Kim HS, "Proteomic analysis of microvesicles derived from human mesenchymal stem cells", J Proteome Res, 11, pp.839~849 (2012)[DOI]

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