Abstract
BackgroundFor an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors. We previously reported that the secretomes of bone marrow-derived mesenchymal stem cells (MSC-CM) contain numerous growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which can affect the cellular characteristics and behavior of regenerating bone cells. We hypothesized that angiogenesis is an important step for bone regeneration, and VEGF is one of the crucial factors in MSC-CM that would enhance its osteogenic potential. In the present study, we focused on VEGF in MSC-CM and evaluated the angiogenic and osteogenic potentials of MSC-CM for bone regeneration.MethodsCytokines in MSC-CM were measured by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were cultured with MSC-CM or MSC-CM with anti-VEGF antibody (MSC-CM + anti-VEGF) for neutralization, and tube formation was evaluated. For the evaluation of bone and blood vessel formation with micro-computed tomography (micro-CT) and for the histological and immunohistochemical analyses, a rat calvarial bone defect model was used.ResultsThe concentrations of IGF-1, VEGF, and TGF-β1 in MSC-CM were 1515.6 ± 211.8 pg/mL, 465.8 ± 108.8 pg/mL, and 339.8 ± 14.4 pg/mL, respectively. Tube formation of HUVECs, bone formation, and blood vessel formation were increased in the MSC-CM group but decreased in the MSC-CM + anti-VEGF group. Histological findings suggested that new bone formation in the entire defect was observed in the MSC-CM group although it was decreased in the MSC-CM + anti-VEGF group. Immunohistochemistry indicated that angiogenesis and migration of endogenous stem cells were much more abundant in the MSC-CM group than in the MSC-CM + anti-VEGF group.ConclusionsVEGF is considered a crucial factor in MSC-CM, and MSC-CM is proposed to be an adequate therapeutic agent for bone regeneration with angiogenesis.
Highlights
For an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors
We have previously reported that the secretomes of mesenchymal stem cells (MSCs) (MSC-CM) contain numerous cytokines such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which can affect the cellular characteristics and behavior of regenerating bone cells [5,6,7]
Growth factors included in MSC-CM In MSC-CM, the concentrations of IGF-1, VEGF, and TGF-β1 were 1515.6 ± 211.8 pg/mL, 465.8 ± 108.8 pg/ mL, and 339.8 ± 14.4 pg/mL, respectively
Summary
For an effective bone graft for reconstruction of the maxillofacial region, an adequate vascular network will be required to supply blood, osteoprogenitor cells, and growth factors. Autogenous bone grafts including particulate cancerous bone marrow (PCBM) and vascularized bone grafts were considered the gold standard for the treatment of bone defects in the maxillofacial region [1] This wellstudied procedure has good prognosis but requires an extra surgery at the donor site, which is an additional burden on the patient. Several bone substitutes are commercially available; these materials without a vascular network are not suitable for larger bone defects due to insufficient blood supply supporting the mesenchymal stem cells (MSCs) and osteoblasts for bone repair and regeneration. From these perspectives, novel bone reconstruction procedures that enable regeneration of the vascular network within the reconstructed area will be required
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