title: Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.
abstract: Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF.
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France Assistance Publique des Hôpitaux de Paris (AP-HP) Département d'Odontologie, Hôpitaux Universitaires PNVS, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gorin
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Gael Y
authors.initials: GY
authors.lastname: Rochefort
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Rumeyza
authors.initials: R
authors.lastname: Bascetin
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Hanru
authors.initials: H
authors.lastname: Ying
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lesieur
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Sadoine
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Nathan
authors.initials: N
authors.lastname: Beckouche
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berndt
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Novais
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lesage
authors.affiliation: INSERM UMR-S1144, Université Paris Descartes-Paris Diderot Sorbonne Paris Cité, AP-HP, Hôpital St. Louis, Unité Claude Kellershohn, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hosten
authors.affiliation: Université Paris Diderot, AP-HP, Hôpital St. Louis, Unité Claude Kellershohn, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Vercellino
authors.affiliation: Université Paris Diderot, AP-HP, Hôpital St. Louis, Unité Claude Kellershohn, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Merlet
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Le-Denmat
authors.affiliation: Institut Cochin, Plateforme Imagerie du vivant, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Marchiol
authors.affiliation: INSERM U1148, Laboratory of Vascular Translational Science, Université Paris Diderot Sorbonne Paris Cité, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, and Département Hospitalo-Universitaire Fibrosis, Inflammation, and Remodeling, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Letourneur
authors.affiliation: INSERM U1148, Laboratory of Vascular Translational Science, Université Paris Diderot Sorbonne Paris Cité, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, and Département Hospitalo-Universitaire Fibrosis, Inflammation, and Remodeling, Paris, France.
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France Assistance Publique des Hôpitaux de Paris (AP-HP) Département d'Odontologie, Hôpitaux Universitaires PNVS, Paris, France.
authors.forename: Sibylle Opsahl
authors.initials: SO
authors.lastname: Vital
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Poliard
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France Assistance Publique des Hôpitaux de Paris (AP-HP) Département d'Odontologie, Hôpitaux Universitaires PNVS, Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Salmon
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France catherine.chaussain@parisdescartes.fr laurent.muller@college-de-france.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.affiliation: EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France Assistance Publique des Hôpitaux de Paris (AP-HP) Département d'Odontologie, Hôpitaux Universitaires PNVS, Paris, France catherine.chaussain@parisdescartes.fr laurent.muller@college-de-france.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chaussain
authors.affiliation: Center for Interdisciplinary Research in Biology, Collège de France, Paris, France Inserm U1050, Paris, France CNRS UMRS 7241, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects; D003782:Dental Pulp / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D023822:Tissue Engineering; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor
keywords: Angiogenesis; Dynamic vascular imaging; Hepatocyte growth factor; Hypoxia; Mesenchymal stem cells; Pulp engineering; Vascular endothelial growth factor