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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.
Significance
The results from the present study show that fibroblast growth factor-2 (FGF-2) priming is more efficient than hypoxia at increasing dental pulp stem cells derived from deciduous teeth (SHED)-induced vascularization compared with nonprimed controls. Together, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both hepatocyte growth factor and vascular endothelial growth factor.
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Details
1 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
2 EA 2496 Pathologies, Imagerie et Biothérapies orofaciales et Plateforme Imagerie du Vivant, Dental School, Université Paris Descartes Sorbonne Paris Cité, Montrouge, France
3 Center for Interdisciplinary Research in Biology, Collège de France, Paris, France; Inserm U1050, Paris, France; CNRS UMRS 7241, Paris, France
4 INSERM UMR-S1144, Université Paris Descartes-Paris Diderot Sorbonne Paris Cité, AP-HP, Hôpital St. Louis, Unité Claude Kellershohn, Paris, France
5 Université Paris Diderot, AP-HP, Hôpital St. Louis, Unité Claude Kellershohn, Paris, France
6 Institut Cochin, Plateforme Imagerie du vivant, Université Paris Descartes Sorbonne Paris Cité, Paris, France
7 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