title: Protein kinase C activation stimulates mesenchymal stem cell adhesion through activation of focal adhesion kinase.
abstract: Emerging evidence suggests that cell therapy with mesenchymal stem cells (MSCs) has beneficial effects on the injured heart. However, the decreased survival and/or adhesion of MSCs under ischemic conditions limits the application of cell transplantation as a therapeutic modality. We investigated a potential method of increasing the adhesion ability of MSCs to improve their efficacy in the ischemic heart. Treatment of MSCs with PKC activator, phorbol 12-myristate 13-acetate (PMA), increased cell adhesion and spreading in a dose-dependent method and significantly decreased detachment. When MSCs were treated with PKC inhibitor, that is, rottlerin, adhesion of MSCs was slightly diminished, and detachment was also decreased compared to the treatment with PMA. MSCs treated with both PMA and rottlerin behaved similarly to normal controls. In 3D matrix cardio gel, treatment with PMA increased the number of MSCs compared to the control group and MSCs treated with rottlerin. Expressions of focal adhesion kinase, cytoskeleton-associated proteins, and integrin subunits were clearly demonstrated in PMA-treated MSCs by immunoblotting and/or immunocytochemistry. The effect of PKC activator treatment on MSCs was validated in vivo. Following injection into rat hearts, the PMA-treated MSCs exhibited significantly higher retention in infarcted myocardium compared to the MSC group. Infarct size, fibrosis area, and apoptotic cells were reduced, and cardiac function was improved in rat hearts injected with PMA-treated MSCs compared to sham and/or MSC-implanted group. These results indicate that PKC activator is a potential target for niche manipulation to enhance adhesion of MSCs for cardiac regeneration.
authors.affiliation: Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byeong-Wook
authors.initials: BW
authors.lastname: Song
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.forename: Bum-Kee
authors.initials: BK
authors.lastname: Hong
authors.forename: Il-Kwon
authors.initials: IK
authors.lastname: Kim
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Cha
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Onju
authors.initials: O
authors.lastname: Ham
authors.forename: Se-Yeon
authors.initials: SY
authors.lastname: Lee
authors.forename: Chang Youn
authors.initials: CY
authors.lastname: Lee
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Eunmi
authors.initials: E
authors.lastname: Choi
authors.forename: Heesang
authors.initials: H
authors.lastname: Song
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D017202:Myocardial Ischemia / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D016023:Integrins; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; C085746:rottlerin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate