Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway.
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.
Peura
Matti
M
Institute of Biomedicine, Pharmacology, Biomedicum, University of Helsinki, Helsinki, Finland.
Bizik
Jozef
J
Salmenperä
Pertteli
P
Noro
Ariel
A
Korhonen
Matti
M
Pätilä
Tommi
T
Vento
Antti
A
Vaheri
Antti
A
Alitalo
Riitta
R
Vuola
Jyrki
J
Harjula
Ari
A
Kankuri
Esko
E
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*
D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met