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Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway |
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| Authors: | Matti Peura MD ; Jozef Bizik PhD DSc ; Pertteli Salmenperä MSc ; Ariel Noro BM ; Matti Korhonen MD PhD ; Tommi Pätilä MD ; Antti Vento MD PhD ; Antti Vaheri MD PhD ; Riitta Alitalo MD PhD ; Jyrki Vuola MD PhD ; Ari Harjula MD PhD ; Esko Kankuri MD PhD |
| Institution: | Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland,; Cell Therapy Research Consortium, 3rd Department of Surgery, Helsinki University Hospital, Helsinki, Finland,; Laboratory of Tumour Cell Biology, Slovak Academy of Sciences, Bratislava, Slovakia,; Department of Virology, Haartman Institute,; Institute of Biomedicine, Anatomy, Biomedicum, University of Helsinki, Helsinki, Finland,; Unit for Pediatric Hemato-Oncology and Bone Marrow Transplantation, Hospital for Children and Adolescents,; HUSLAB, Stem Cell Laboratory, and; Helsinki Burn Centre, Helsinki University Hospital, Helsinki, Finland |
| 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. |
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