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Objectives: Angiogenesis and osteogenesis are essential for bone growth, fracture repair, and bone remodeling. Vascular endothelial growth factor (VEGF) has an important role in bone repair by promoting angiogenesis and osteogenesis. In our previous study, endothelial progenitor cells (EPCs) promoted bone healing in a rat segmental bone defect as confirmed by radiological, histological, biomechanical, and micro-CT evaluations. Although EPCs have demonstrated effectiveness in animal models of fracture healing, the mechanism by which EPCs enhance fracture healing remains unclear. We hypothesized a possible paracrine mechanism of action, where the secretion of growth factors critical to the processes of fracture healing (such as VEGF), is responsible for the positive effects of EPC therapy. The purpose of this study was to evaluate VEGF gene expression after local EPC therapy for a rat segmental bone defect., Methods: Rat bone marrow-derived EPCs were isolated by the Ficoll-paque gradient centrifuge technique. The EPCs were cultured for 7-10 days in endothelial cell growth medium with supplements and collected for treatment of the rat segmental bone defect. EPCs were identified by immunocytochemistry staining with primary antibodies for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor. A total of 56 rats were studied. A 5-mL segmental bone defect was created in the middle one-third of each femur followed by miniplate fixation. The treatment group received 1 × 10 EPCs locally at the bone defect on a gelfoam scaffold and control animals received the gelfoam scaffold only. Seven control and 7 EPC-treated rats were included in each group at 1, 2, 3, and 10 weeks. The animals were sacrificed at the end of the treatment period, and specimens from the fracture gap area were collected and immediately frozen. Rat VEGF mRNA was measured by reverse-transcriptase-polymerase chain reaction and quantified by VisionWorksLS. All measurements were performed in triplicate., Results: Cultured EPCs at 1 week showed positive staining for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor markers. The EPC group had a greater VEGF expression than the control group at weeks 1, 2, and 3, but not at week 10. Three VEGF isoforms were detected in this rat model: VEGF120, VEGF164, and VEGF188. VEGF120 and VEGF164 levels peaked at 2 weeks, whereas VEGF188 levels peaked at 3 weeks. All 3 VEGF isoform levels were low at 10 weeks., Discussion and Conclusions: EPC-based therapy for a segmental bone defect results in increased VEGF expression during the early period of fracture repair. In addition, the specific VEGF isoform may be a key regulator of the bone healing process. These findings demonstrate that EPCs may promote fracture healing by increasing VEGF levels and thus stimulating angiogenesis, a process that is essential for early callus formation and bone regeneration.

Purpose: The purpose of this article was to analyze the results of studies in the literature, which evaluated the use of endothelial progenitor cells (EPCs) as a cell-based tissue engineering strategy., Methods: EPCs have been successfully used in regenerative medicine to augment neovascularization in patients after myocardial infarction and limb ischemia. EPCs' important role as vasculogenic progenitors presents them as a potential source for cell-based therapies to promote bone healing., Results: EPCs have been shown to have prominent effects in promoting bone regeneration in several animal models. Evidence indicates that EPCs promote bone regeneration by stimulating both angiogenesis and osteogenesis through a differentiation process toward endothelial cell lineage and formation of osteoblasts. Moreover, EPCs increase vascularization and osteogenesis by increased secretion of growth factors and cytokines through paracrine mechanisms., Conclusion: EPCs offer the potential to emerge as a new strategy among other cell-based therapies to promote bone regeneration. Further investigations and human trials are required to address current questions with regard to biology and mechanisms of action of EPCs in bone tissue engineering.

Purpose: Local treatment of segmental bone defects with ex vivo expanded endothelial progenitor cells (EPCs) has been shown to increase osteogenesis and callus formation in rat femur diaphyseal defects. The purpose of this study was to evaluate the effects of local EPC therapy on the microarchitecture and biomechanical properties of a segmental bone defect in a rat model., Methods: Five-millimeter segmental defects were created in the femora of 14 Fisher 344 rats and stabilized with miniplates. The treatment group (n = 7) received 1 × 10(6) EPCs, seeded on a Gelfoam scaffold, locally at the site of the bone defect, and control animals (n = 7) received Gelfoam and saline only. Animals were euthanized 10 weeks after the procedure and new bone formation was assessed with radiographs, microcomputed tomography and biomechanical testing., Results: Radiographically, all the animals in the EPC-treated group healed with bridging callus formation, whereas animals in the control group developed nonunion of the defect. Microcomputed tomography assessment demonstrated significantly superior bone formation in the EPC-treated group versus the control group for all parameters tested (P = 0.013-0.000). Biomechanical testing revealed that the EPC-treated group had significantly higher torsional strength (P = 0.000) and stiffness (P = 0.000) when compared with the control group., Conclusion: The results of this study suggest that local EPC therapy significantly enhances fracture healing in a segmental defect model in a rat femur. EPC therapy results in superior radiographic bone formation and healing when compared with appropriate controls.

Endothelial progenitor cells (EPCs) derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+) cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury. [ABSTRACT FROM AUTHOR]