title: Endothelial differentiation of SHED requires MEK1/ERK signaling.
abstract: The discovery that dental pulp stem cells are capable of differentiating into endothelial cells raises the exciting possibility that these cells can be a single source of odontoblasts and vascular networks in dental tissue engineering. The purpose of this study was to begin to define signaling pathways that regulate endothelial differentiation of SHED. Stem cells from exfoliated deciduous teeth (SHED) exposed to endothelial growth medium (EGM-2MV) supplemented with vascular endothelial growth factor (VEGF) differentiated into VEGFR2-positive and CD31-positive endothelial cells in vitro. In vivo, VEGFR1-silenced SHED seeded in tooth slice/ scaffolds and transplanted into immunodeficient mice showed a reduction in human CD31-positive blood vessels as compared with controls (p = 0.02). Exposure of SHED to EGM2-MV supplemented with VEGF induced potent activation of ERK and Akt signaling, while it inhibited phosphorylation of STAT3. Notably, genetic (MEK1 silencing) or chemical (U0126) inhibition of ERK signaling restored constitutive STAT3 phosphorylation and inhibited the differentiation of SHED into endothelial cells. Collectively, analysis of these data unveiled the VEGF/MEK1/ERK signaling pathway as a key regulator of the endothelial differentiation of dental pulp stem cells.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA.
authors.forename: L W
authors.initials: LW
authors.lastname: Bento
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Imai
authors.forename: F
authors.initials: F
authors.lastname: Nör
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: F B
authors.initials: FB
authors.lastname: Araujo
authors.forename: J E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D003470:Culture Media; D003782:Dental Pulp / Q000166:cytology*; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000187:drug effects; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D013234:Stem Cells / Q000502:physiology*; D054457:Tissue Scaffolds; D014094:Tooth, Deciduous / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
chemical_list: D002070:Butadienes; D003470:Culture Media; D004791:Enzyme Inhibitors; D009570:Nitriles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C113580:U 0126; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051058:Oncogene Protein v-akt; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1