title: hMSC-Derived VEGF Release Triggers the Chemoattraction of Alveolar Osteoblasts.
abstract: Human mesenchymal stem cells (hMSCs) are promising candidates for regenerative periodontal strategies, due to the broad spectrum of supportive effects on cells and tissues at the site of application. Although positive effects are visible, the understanding of their underlying mechanisms still requires further elucidation. Recently, we have shown that hMSCs are capable to prompt osteogenic differentiation of alveolar osteoblasts, thereby presumably contributing to alveolar bone regeneration. Another issue that is critical in this context is the attraction of hard tissue-forming cells to regeneration sites, but it is an open question whether hMSCs can afford this. In the present manuscript, we show by life cell imaging that in interactive cocultures, hMSCs successfully trigger osteoblast chemotaxis. Gene expression analysis for hMSC-innate chemoattractive biomolecules, orchestrating this process, revealed vascular endothelial growth factor (VEGF), PgE synthase, osteoprotegerin (OPG), monocyte colony-stimulating factor, and transforming growth factor β1, which was confirmed for VEGF and OPG on the protein level. Noteworthy, we showed that only corresponding levels of VEGF but not OPG attracted alveolar osteoblasts similar to hMSC coculture, while VEGF inhibitor abolished both the VEGF and the hMSC-triggered chemoattraction. In summary, we have identified secreted OPG and VEGF proteins as potential chemoattractants, of which further characterization yielded VEGF as a causative for hMSC-directed osteoblast chemotaxis. With respect to the better understanding of potential hMSC-based periodontal regeneration strategies, we propose hMSC-derived VEGF release as a mechanism in the recruitment of hard tissue-forming cells to alveolar bone sites in need of regeneration.
authors.affiliation: Department of Operative Dentistry and Periodontology, University Medical Centre Freiburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Proksch
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Centre Freiburg, Germany.
authors.forename: Gido
authors.initials: G
authors.lastname: Bittermann
authors.affiliation: Department of Medical Biometry and Medical Informatics, Division of Data Analysis and Modelling, University Medical Centre Freiburg, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Vach
authors.affiliation: Centre for Biological Systems Analysis, Life Imaging Center, Albert-Ludwigs-University Freiburg, Germany.|BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Nitschke
authors.affiliation: Department of Oral Biotechnology, Centre for Dental Medicine, University Medical Centre Freiburg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Tomakidi
authors.affiliation: Department of Operative Dentistry and Periodontology, University Medical Centre Freiburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Hellwig
mesh_terms: D016301:Alveolar Bone Loss / Q000473:pathology / Q000628:therapy*; D001861:Bone Regeneration / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002633:Chemotaxis / Q000235:genetics; D018920:Coculture Techniques; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Chemotaxis (MeSH ID D002633); Mesenchymal stem cells (MeSH ID D059630); Osteoblasts (MeSH ID D010006); Vascular endothelial growth factor (MeSH ID D042461)