title: Angiogenic Potential and Secretome of Human Apical Papilla Mesenchymal Stem Cells in Various Stress Microenvironments.
abstract: Stem cells from the apical papilla (SCAP) of human adult teeth are considered an accessible source of cells with angiogenic properties. The aims of this study were to investigate the endothelial transdifferentiation of SCAP, the secretion of pro- and antiangiogenic factors from SCAP, and the paracrine effects of SCAP when exposed to environmental stress to stimulate tissue damage. SCAP were exposed to serum deprivation (SD), glucose deprivation (GD), and oxygen deprivation/hypoxia (OD) conditions, individually or in combination. Endothelial transdifferentiation was evaluated by in vitro capillary-like formation assays, real-time polymerase chain reaction, western blot, and flow cytometric analyses of angiogenesis-related markers; secretome by antibody arrays and enzyme-linked immunosorbent assays (ELISA); and paracrine impact on human umbilical vein endothelial cells (HUVECs) by in vitro transwell migration and capillary-like formation assays. The short-term exposure of SCAP to glucose/oxygen deprivation (GOD) in the presence, but mainly in deprivation, of serum (SGOD) elicited a proangiogenesis effect indicated by expression of angiogenesis-related genes involved in vascular endothelial growth factor (VEGF)/VEGFR and angiopoietins/Tie pathways. This effect was unachievable under SD in normoxia, suggesting that the critical microenvironmental condition inducing rapid endothelial shift of SCAP is the combination of SGOD. Interestingly, SCAP showed high adaptability to these adverse conditions, retaining cell viability and acquiring a capillary-forming phenotype. SCAP secreted higher numbers and amounts of pro- (angiogenin, IGFBP-3, VEGF) and lower amounts of antiangiogenic factors (serpin-E1, TIMP-1, TSP-1) under SGOD compared with SOD or SD alone. Finally, secretome obtained under SGOD was most effective in inducing migration and capillary-like formation by HUVECs. These data provide new evidence on the microenvironmental factors favoring endothelial transdifferentiation of SCAP, uncovering the molecular mechanisms regulating their fate. They also validate the angiogenic properties of their secretome giving insights into preconditioning strategies enhancing their therapeutic potential.
authors.affiliation: 1 Department of Fixed Prosthesis and Implant Prosthodontics, School of Dentistry, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .|2 Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School (MHH) , Hannover, Germany .
authors.forename: Athina
authors.initials: A
authors.lastname: Bakopoulou
authors.affiliation: 3 Department of Physiology and Pharmacology, School of Medicine, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Kritis
authors.affiliation: 4 Department of Oral Medicine and Pathology, School of Dentistry, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Andreadis
authors.affiliation: 1 Department of Fixed Prosthesis and Implant Prosthodontics, School of Dentistry, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .
authors.forename: Eleni
authors.initials: E
authors.lastname: Papachristou
authors.affiliation: 2 Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School (MHH) , Hannover, Germany .
authors.forename: Gabriele
authors.initials: G
authors.lastname: Leyhausen
authors.affiliation: 1 Department of Fixed Prosthesis and Implant Prosthodontics, School of Dentistry, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .
authors.forename: Petros
authors.initials: P
authors.lastname: Koidis
authors.affiliation: 2 Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School (MHH) , Hannover, Germany .
authors.forename: Werner
authors.initials: W
authors.lastname: Geurtsen
authors.affiliation: 5 Laboratory of Pharmacology, School of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.) , Thessaloniki, Greece .
authors.forename: Asterios
authors.initials: A
authors.lastname: Tsiftsoglou
mesh_terms: D000293:Adolescent; D015687:Cell Hypoxia / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology*; D060833:Cellular Microenvironment / Q000502:physiology*; D003771:Dental Papilla / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: D042461:Vascular Endothelial Growth Factor A