Submitted on July 25, 2006
Accepted on March 1, 2007
Tissue-Specific Stem Cells
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Tissue transglutaminase is essential for integrin-mediated survival of bone marrow-derived mesenchymal stem cells
Heesang Song 1,
Woochul Chang 1,
Soyeon Lim 1,
Hye-Sun Seo 1,
Chi Young Shim 1,
Sungha Park 1,
Yung-Jong Yoo 2,
Byung-Soo Kim 3,
Byoung-Hyun Min 4,
Hakbae Lee 5,
Yangsoo Jang 1,
Namsik Chung 1,
Ki-Chul Hwang 1*
1 Cardiovascular Research Institute, Cardiology Division, Yonsei University College of Medicine, Seoul, Korea
2 Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
3 Department of Chemical Engineering, Hanyang University, Seoul, Korea
4 Department of Orthopedic Surgery, Ajou University, Suwon, Korea
5 Department of Applied Statistics, Yonsei University, Seoul, Korea
* To whom correspondence should be addressed. E-mail: kchwang{at}yumc.yonsei.ac.kr.
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Abstract |
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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 pro-survival modification strategy, we genetically engineered MSCs to over-express tissue transglutaminase (tTG), with intention to enhance adhesion and ultimately cell survival after implantation. tTG-transfected MSCs showed a 2.7-fold and greater than a 2-fold 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 3D matrix, showed a 33.1% increase. Down-regulation of tTG by transfection of small interfering RNA (siRNA) 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 106 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 to MSC transplantation alone. These findings suggested that tTG may play an important role in integrin-mediated adhesion of MSCs in implanted tissues.
Key Words.
Adhesion, Tissue transglutaminase, Integrin, Mesenchymal stem cell
