title: Modulation of MAPK signalling by immobilized adhesive peptides: Effect on stem cell response to BMP-9-derived peptides.
abstract: Biomimetic materials were developed to regulate stem cell behaviour. We have analyzed the influence of polycaprolactone (PCL) films, functionalized with adhesive peptides derived from fibronectin (pFibro) or bone sialoprotein (pBSP), on the response of murine multipotent C3H10T1/2 cells to bone morphogenetic protein-9 (BMP-9) and its derived peptides (pBMP-9 and SpBMP-9). PCL-pFibro promoted better cell cytoskeleton organization and faster focal adhesion kinase activation than did PCL-pBSP. PCL-pFibro also promoted MAPK signalling to improve the cell response to BMP-9 by inactivating ERK1/2 and stimulating p38 and JNK. BMP-9, pBMP-9 and SpBMP-9 induced greater phosphorylation of Smad1/5/8 in cells attached to PCL-pFibro than in cells on PCL-pBSP. These phosphorylated Smad1/5/8 were translocated to the nucleus. BMP-9 and its derived peptides restored the phosphorylation of JNK in cells on PCL-pBSP, but it remained less phosphorylated than in cells on PCL-pFibro stimulated with pBMP-9 and SpBMP-9. Cells attached to PCL-pFibro contained more Runx2, essential for stem cell commitment to become osteoblasts, than did cells on PCL-pBSP when incubated with BMP-9 and its derived peptides. Runx2 was no longer detected when the cells were pre-treated with JNK inhibitor. Therefore pFibro plus BMP-9 and its derived peptides may be a promising strategy to develop biomimetic materials.
  
  
  CONCLUSIONS
  Biomaterials functionalized with adhesive peptides to favour bone repair have generated a great interest over the past decade. However, the effect of these materials on the ability of cells to respond to growth factors remains poorly known. One major growth factor subfamily involved in bone formation is the bone morphogenetic protein (BMP). However, these BMPs are expensive. We therefore developed less costly derived molecules. We showed how adhesive peptides derived from bone matrix proteins grafted onto polymer films affect the intracellular signalling and thus the ability of stem cells to be activated by BMP and its derived molecules. We have therefore identified a combination of bioactive polymers and BMP molecules that direct the stem cells towards bone forming cells.
authors.affiliation: Cells-Biomaterials Biohybrid Systems, Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, 2500, Université Blvd, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Beauvais
authors.affiliation: Cells-Biomaterials Biohybrid Systems, Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, 2500, Université Blvd, Sherbrooke, Québec J1K 2R1, Canada; École Polytechnique de Montréal, 2900, Blvd Édouard Montpetit, Montréal, Québec H3C 3A7, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Drevelle
authors.affiliation: Cells-Biomaterials Biohybrid Systems, Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, 2500, Université Blvd, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Lauzon
authors.affiliation: Cells-Biomaterials Biohybrid Systems, Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, 2500, Université Blvd, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Daviau
authors.affiliation: Cells-Biomaterials Biohybrid Systems, Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, 2500, Université Blvd, Sherbrooke, Québec J1K 2R1, Canada. Electronic address: Nathalie.Faucheux@usherbrooke.ca.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faucheux
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D032701:Biomimetics; D002467:Cell Nucleus / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D058574:Integrin-Binding Sialoprotein / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D051379:Mice; D008809:Mice, Inbred C3H; D010006:Osteoblasts / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D016596:Vinculin / Q000737:chemistry
chemical_list: D000199:Actins; D001672:Biocompatible Materials; D050659:Core Binding Factor Alpha 1 Subunit; D005353:Fibronectins; D058574:Integrin-Binding Sialoprotein; D010455:Peptides; D011091:Polyesters; D011108:Polymers; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; D016596:Vinculin; C016240:polycaprolactone; D004247:DNA; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Bone morphogenetic proteins; Cell signalling; Integrin; Runx2