Abstract
Regenerative medicine for bone tissue mainly depends on efficient recruitment of endogenous or transplanted stem cells to guide bone regeneration. Platelet-derived growth factor (PDGF) is a functional factor that has been widely used in tissue regeneration and repair. However, the short half-life of PDGF limits its efficacy, and the mechanism by which PDGF regulates stem cell-based bone regeneration still needs to be elucidated. In this study, we established genetically modified PDGF-B-overexpressing bone marrow stromal cells (BMSCs) using a lentiviral vector and then explored the mechanism by which PDGF-BB regulates BMSC-based vascularized bone regeneration. Our results demonstrated that PDGF-BB increased osteogenic differentiation but inhibited adipogenic differentiation of BMSCs via the extracellular signal-related kinase 1/2 (ERK1/2) signaling pathway. In addition, secreted PDGF-BB significantly enhanced human umbilical vein endothelial cell (HUVEC) migration and angiogenesis via the phosphatidylinositol 3 kinase (PI3K)/AKT and ERK1/2 signaling pathways. We evaluated the effect of PDGF-B-modified BMSCs on bone regeneration using a critical-sized rat calvarial defect model. Radiography, micro-CT, and histological analyses revealed that PDGF-BB overexpression improved BMSC-mediated angiogenesis and osteogenesis during bone regeneration. These results suggest that PDGF-BB facilitates BMSC-based bone regeneration by enhancing the osteogenic and angiogenic abilities of BMSCs.
Highlights
Reconstruction of bony defects caused by infection, trauma, or tumor resection is still a substantial clinical challenge
Both real-time RT-PCR and Western blotting results indicated that the expression of Platelet-derived growth factor (PDGF)-BB in Bone marrow stromal cells (BMSCs) was significantly upregulated after gene transduction in the Lenti-PDGF group (Figure 1(c), Figure 1(d))
Our results demonstrated that overexpression of PDGF-BB in BMSCs increases osteogenic differentiation while inhibiting adipogenic differentiation via the extracellular signal-related kinase 1/2 (ERK1/2) signaling pathway
Summary
Reconstruction of bony defects caused by infection, trauma, or tumor resection is still a substantial clinical challenge. Bone marrow stromal cells (BMSCs) possessing regenerative potential have been considered an ideal cell source for bone regeneration [1, 2]. The combination of BMSCs with particular growth factors, such as bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF), has been considered a promising strategy for bone tissue regeneration [3]. Platelet-derived growth factor (PDGF), a two-chain polypeptide, was originally identified in platelets [4, 5], and there are five polypeptide isoforms: PDGF-AA, PDGF-AB, PDGF-. BB, PDGF-CC, and PDGF-DD [5, 6] Among these isoforms, PDGF-BB is a unique ligand that can interact with all three PDGF receptors, namely, PDGFR-αα, PDGFR-αβ, and PDGFR-ββ [4]. PDGF-BB is a potent mitogen [7, 8] and
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