title: Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation.
abstract: Transplantation using stem cells including bone marrow mesenchymal stem cells (BMSCs) is emerging as a potential regenerative therapy after ischemic attacks in the heart and brain. The migration capability of transplanted cells is a critical cellular function for tissue repair. Based on our recent observations that hypoxic preconditioning (HP) has multiple benefits in improving stem cell therapy and that the potassium Kv2.1 channel acts as a promoter for focal adhesion kinase (FAK) activation and cell motility, the present investigation tested the hypothesis that HP treatment can increase BMSC migration via the mechanism of increased Kv2.1 expression and FAK activities. BMSCs derived from green fluorescent protein-transgenic mice were treated under either normoxic (N-BMSC) or hypoxic (0.5% O(2)) (HP-BMSC) conditions for 24 h. Western blot analysis showed HP selectively upregulated Kv2.1 expression while leaving other K(+) channels, such as Kv1.5 and Kv1.4, unaffected. Compared with normoxic controls, significantly larger outward delayed rectifier K(+) currents were recorded in HP-BMSCs. HP enhanced BMSC migration/homing activities in vitro and after intravenous transplantation into rats subjected to permanent myocardial infarction (MI). The HP-promoted BMSC migration was inhibited by either blocking K(+) channels or knocking down Kv2.1. Supporting a relationship among HP, Kv2.1, and FAK activation, HP increased phosphorylation of FAK(397) and FAK(576/577), and this effect was antagonized by blocking K(+) channels. These findings provide novel evidence that HP enhances the ability of BMSCs to migrate and home to the injured region; this effect is mediated through a regulatory role of Kv2.1 on FAK phosphorylation/activation.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Tammi M
authors.initials: TM
authors.lastname: Taylor
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wei
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D055647:Rats, Transgenic; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D014945:Wound Healing / Q000187:drug effects
chemical_list: C496990:Kcnb1 protein, mouse; C496991:Kcnb1 protein, rat; D026902:Potassium Channel Blockers; D051669:Shab Potassium Channels; D049452:Green Fluorescent Proteins; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat