Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells.
Using human MSCs (mesenchymal stem cells) lacking VEGF (vascular endothelial growth factor) receptors, we show that the pro-angiogenic receptor neuropilin-1 associates with phosphorylated PDGFRs [PDGF (platelet-derived growth factor) receptors], thereby regulating cell signalling, migration, proliferation and network assembly. Neuropilin-1 co-immunoprecipitated and co-localized with phosphorylated PDGFRs in the presence of growth factors. Neuropilin-1 knockdown blocked PDGF-AA-induced PDGFRalpha phosphorylation and migration, reduced PDGF-BB-induced PDGFRbeta activation and migration, blocked VEGF-A activation of both PDGFRs, and attenuated proliferation. Neuropilin-1 prominently co-localized with both PDGFRs within MSC networks assembled in Matrigel and in the chorioallantoic membrane vasculature microenvironment, and its knockdown grossly disrupted network assembly and decreased PDGFR signalling. Thus neuropilin-1 regulates MSCs by forming ligand-specific receptor complexes that direct PDGFR signalling, especially the PDGFRalpha homodimer. This receptor cross-talk may control the mobilization of MSCs in neovascularization and tissue remodelling.
Ball
Stephen G
SG
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M139PT, U.K.
Bayley
Christopher
C
Shuttleworth
C Adrian
CA
Kielty
Cay M
CM
D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D039942:Neuropilin-1; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta