title: VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.
abstract: The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-β (TGF-β)-responsive SG‑2 cells, bone morphogenetic protein (BMP)-responsive SG‑3 cells, and TGF-β/BMP-non-responsive SG‑5 cells], derived from the bone marrow of green fluorescent protein-transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-β-responsive SG‑2 cells. Among the genes that were highly expressed in the SG‑2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS-like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG‑2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-β significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG‑2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-β reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs.
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Chosa
authors.affiliation: Division of Periodontology, Department of Conservative Dentistry, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sawada
authors.affiliation: Department of Prosthodontics and Oral Implantology, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan.
authors.forename: Hisatomo
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Division of Periodontology, Department of Conservative Dentistry, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yaegashi
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D042601:Lymphatic Vessels / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D010766:Phosphorylation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D048049:Extracellular Signal-Regulated MAP Kinases