title: Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway.
abstract: We previously showed cell-cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved.
authors.affiliation: Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Peura
authors.forename: Jozef
authors.initials: J
authors.lastname: Bizik
authors.forename: Pertteli
authors.initials: P
authors.lastname: Salmenperä
authors.forename: Ariel
authors.initials: A
authors.lastname: Noro
authors.forename: Matti
authors.initials: M
authors.lastname: Korhonen
authors.forename: Tommi
authors.initials: T
authors.lastname: Pätilä
authors.forename: Antti
authors.initials: A
authors.lastname: Vento
authors.forename: Antti
authors.initials: A
authors.lastname: Vaheri
authors.forename: Riitta
authors.initials: R
authors.lastname: Alitalo
authors.forename: Jyrki
authors.initials: J
authors.lastname: Vuola
authors.forename: Ari
authors.initials: A
authors.lastname: Harjula
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
mesh_terms: D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D002468:Cell Physiological Phenomena / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology*
chemical_list: D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met