title: VEGF Enhances the Migration of MSCs in Neural Differentiation by Regulating Focal Adhesion Turnover.
abstract: Mesenchymal stem cells (MSCs) hold great promise in neural regeneration, due to their intrinsic neuronal potential and migratory tropism to damaged nervous tissues. However, the chemotactic signals mediating the migration of MSCs remain poorly understood. Here, we investigated the regulatory roles for focal adhesion kinase (FAK) and Rac1 in vascular endothelial growth factor (VEGF)-stimulated migration of MSCs in neural differentiation. We found that MSCs in various differentiation states show significant different chemotactic responses to VEGF and cells in 24-h preinduction state possess the highest migration speed and efficiency. FAK, as the downstream signaling molecule, is involved in the VEGF-induced migration by regulating the assembly and distribution of focal adhesions (FAs) and reorganization of F-actin. The features of FAs and cytoskeletons and the ability of lamellipodia formation are closely related to the neural differentiation states of MSCs. VEGF promotes FA formation with an asymmetric distribution of FAs and induces the activation of Y397-FAK and Y31/118-paxillin of undifferentiated and 24-h preinduced MSCs in a time-dependent manner. Inhibition of FAK by PF-228 or expressing FAK-Y397F mutant impairs the dynamics of FAs in MSCs during VEGF-induced migration. Furthermore, Rac1 regulates FA formation in a FAK-dependent manner. Overexpression of constitutive activated mutants of Rac1 increases the number of FAs in undifferentiated and 24-h preinduced MSCs, while VEGF-induced increase of FA formation is decreased by inhibiting FAK by PF-228. Collectively, these results demonstrate that FAK and Rac1 signalings coordinately regulate the dynamics of FAs during VEGF-induced migration of MSCs in varying neural differentiation states.
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Xingkai
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Ya'nan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Suzhou, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D022001:Focal Adhesions / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009416:Nerve Regeneration / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D000199:Actins; D015363:Quinolones; D013450:Sulfones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051416:Focal Adhesion Protein-Tyrosine Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein