title: Tissue transglutaminase is essential for integrin-mediated survival of bone marrow-derived mesenchymal stem cells.
abstract: Autologous mesenchymal stem cell (MSC) transplantation therapy for repair of myocardial injury has inherent limitations due to the poor viability of the stem cells after cell transplantation. Adhesion is a prerequisite for cell survival and also a key factor for the differentiation of MSCs. As a novel prosurvival modification strategy, we genetically engineered MSCs to overexpress tissue transglutaminase (tTG), with intention to enhance adhesion and ultimately cell survival after implantation. tTG-transfected MSCs (tTG-MSCs) showed a 2.7-fold and greater than a twofold increase of tTG expression and surface tTG activity, respectively, leading to a 20% increased adhesion of MSCs on fibronectin (Fn). Spreading and migration of tTG-MSCs were increased 4.75% and 2.52%, respectively. Adhesion of tTG-MSCs on cardiogel, a cardiac fibroblast-derived three-dimensional matrix, showed a 33.1% increase. Downregulation of tTG by transfection of small interfering RNA specific to the tTG resulted in markedly decreased adhesion and spread of MSCs on Fn or cardiogel. tTG-MSCs on Fn significantly increased phosphorylation of focal adhesion related kinases FAK, Src, and PI3K. tTG-MSCs showed significant retention in infarcted myocardium by forming a focal adhesion complex and developed into cardiac myocyte-like cells by the expression of cardiac-specific proteins. Transplantation of 1 x 10(6) MSCs transduced with tTG into the ischemic rat myocardium restored normalized systolic and diastolic cardiac function. tTG-MSCs further restored cardiac function of infarcted myocardium as compared with MSC transplantation alone. These findings suggested that tTG may play an important role in integrin-mediated adhesion of MSCs in implanted tissues. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Cardiovascular Research Institute, Cardiology Division, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Heesang
authors.initials: H
authors.lastname: Song
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Hye-Sun
authors.initials: HS
authors.lastname: Seo
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Shim
authors.forename: Sungha
authors.initials: S
authors.lastname: Park
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Yoo
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Kim
authors.forename: Byoung-Hyun
authors.initials: BH
authors.lastname: Min
authors.forename: Hakbae
authors.initials: H
authors.lastname: Lee
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Namsik
authors.initials: N
authors.lastname: Chung
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006321:Heart / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D016023:Integrins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins