Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex.
The integrity of transplanted mesenchymal stem cells (MSCs) for cardiac regeneration is dependent on cell-cell or cell-matrix adhesion, which is inhibited by reactive oxygen species (ROS) generated in ischemic surroundings after myocardial infarction. Intracellular ROS play a key role in the regulation of cell adhesion, migration, and proliferation. This study was designed to investigate the role of ROS on MSC adhesion. In H(2)O(2) treated MSCs, adhesion and spreading were inhibited and detachment was increased in a dose-dependent manner, and these effects were significantly rescued by co-treatment with the free radical scavenger, N-acetyl-L-cysteine (NAC, 1 mM). A similar pattern was observed on plates coated with different matrices such as fibronectin and cardiogel. Hydrogen peroxide treatment resulted in a marked decrease in the level of focal adhesion-related molecules, such as phospho-FAK and p-Src in MSCs. We also observed a significant decrease in the integrin-related adhesion molecules, alpha V and beta1, in H(2)O(2) treated MSCs. When injected into infarcted hearts, the adhesion of MSCs co-injected with NAC to the border region was significantly improved. Consequently, we observed that fibrosis and infarct size were reduced in MSC and NAC-injected rat hearts compared to in MSC-only injected hearts. These results indicate that ROS inhibit cellular adhesion of engrafted MSCs and provide evidence that the elimination of ROS might be a novel strategy for improving the survival of engrafted MSCs.
Song
Heesang
H
Research Institute of Science for Aging, Seoul, Republic of Korea.
Cha
Min-Ji
MJ
Song
Byeong-Wook
BW
Kim
Il-Kwon
IK
Chang
Woochul
W
Lim
Soyeon
S
Choi
Eun Ju
EJ
Ham
Onju
O
Lee
Se-Yeon
SY
Chung
Namsik
N
Jang
Yangsoo
Y
Hwang
Ki-Chul
KC
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051417:Focal Adhesion Kinase 1 / Q000187:drug effects / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006085:Graft Survival / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016166:Free Radical Scavengers; D016023:Integrins; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D000111:Acetylcysteine