title: VEGFR2-dependent angiogenic capacity of pericyte-like dental pulp stem cells.
abstract: Dental pulp stem cells (DPSCs) have previously demonstrated potential pericyte-like topography and function. However, the mechanisms regulating their pericyte function are still unknown. In this study, murine DPSC angiogenic and pericyte function were investigated. Tie2-GFP mouse DPSCs were negative for GFP, indicating the absence of endothelial cells in DPSC cultures. Endothelial cells co-cultured with DPSCs formed more mature in vitro tube-like structures as compared with those co-cultured with bone marrow stromal cells (BMSCs). Many DPSCs were located adjacent to vascular tubes, assuming a pericyte location. Subcutaneous DPSC transplants in mice with matrigel (MG) (DPSC-MG) induced more vessel formation than BMSC-MG. Soluble Flt (sFlt), an angiogenic inhibitor that binds VEGF-A, significantly decreased the amount of blood vessels in DPSC-MG, but not in BMSC-MG. sFlt inhibited VEGFR2 and downstream ERK signaling in DPSCs. Similar to sFlt inhibition, VEGFR2 knockdown in DPSCs resulted in down-regulation of Vegfa, Vegf receptors, and EphrinB2 and decreased angiogenic induction of DPSCs in vivo. Therefore, the capacity of DPSCs to induce angiogenesis is VEGFR2-dependent. DPSCs enhance angiogenesis by secreting VEGF ligands and associating with vessels resembling pericyte-like cells. This study provides first insights into the mechanism(s) of DPSC angiogenic induction and their function as pericytes, crucial aspects for DPSC use in tissue regeneration.
authors.affiliation: Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Janebodin
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: W
authors.initials: W
authors.lastname: Buranaphatthana
authors.forename: N
authors.initials: N
authors.lastname: Ieronimakis
authors.forename: M
authors.initials: M
authors.lastname: Reyes
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D018929:Cell Culture Techniques; D018920:Coculture Techniques; D003094:Collagen; D003782:Dental Pulp / Q000166:cytology*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000502:physiology; D036388:Ephrin-B2 / Q000187:drug effects; D005109:Extracellular Matrix; D006801:Humans; D007797:Laminin; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000502:physiology; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D018482:Muscle, Skeletal / Q000601:surgery; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D020286:Pericytes / Q000187:drug effects / Q000502:physiology*; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology*; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D036388:Ephrin-B2; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C059485:matrigel; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; C079086:Tek protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: adult stem cells; angiogenesis; neovascularization; neural crest; soluble Flt; vascular endothelial growth factor