title: Osteogenic graft vascularization and bone resorption by VEGF-expressing human mesenchymal progenitors.
abstract: Rapid vascularisation of tissue-engineered osteogenic grafts is a major obstacle in the development of regenerative medicine approaches for bone repair. Vascular endothelial growth factor (VEGF) is the master regulator of vascular growth. We investigated a cell-based gene therapy approach to generate osteogenic grafts with an increased vascularization potential in an ectopic nude rat model in vivo, by genetically modifying human bone marrow-derived stromal/stem cells (BMSC) to express rat VEGF. BMSC were loaded onto silicate-substituted apatite granules, which are a clinically established osteo-conductive material. Eight weeks after implantation, the vascular density of constructs seeded with VEGF-BMSC was 3-fold greater than with control cells, consisting of physiologically structured vascular networks with both conductance vessels and capillaries. However, VEGF specifically caused a global reduction in bone quantity, which consisted of thin trabeculae of immature matrix. VEGF did not impair BMSC engraftment in vivo, but strongly increased the recruitment of TRAP- and Cathepsin K-positive osteoclasts. These data suggest that VEGF over-expression is effective to improve the vascularization of osteogenic grafts, but also has the potential to disrupt bone homoeostasis towards excessive degradation, posing a challenge to its clinical application in bone tissue engineering.
authors.affiliation: Cell and Gene Therapy, Department of Biomedicine, Basel University Hospital and Basel University, Basel, Switzerland.
authors.forename: Uta
authors.initials: U
authors.lastname: Helmrich
authors.forename: Nunzia
authors.initials: N
authors.lastname: Di Maggio
authors.forename: Sinan
authors.initials: S
authors.lastname: Güven
authors.forename: Elena
authors.initials: E
authors.lastname: Groppa
authors.forename: Ludovic
authors.initials: L
authors.lastname: Melly
authors.forename: Rene D
authors.initials: RD
authors.lastname: Largo
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.forename: Ivan
authors.initials: I
authors.lastname: Martin
authors.forename: Arnaud
authors.initials: A
authors.lastname: Scherberich
authors.forename: Andrea
authors.initials: A
authors.lastname: Banfi
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001857:Bone Matrix / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology*; D056657:Cathepsin K / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010010:Osteoclasts / Q000473:pathology; D010012:Osteogenesis; D051381:Rats; D000071681:Tartrate-Resistant Acid Phosphatase; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D042461:Vascular Endothelial Growth Factor A; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K