Ho, C.-Y.; (2011) Effects of stromal cell-derived factor-1 on the differentiation of stem cells and their role in fracture healing. Doctoral thesis , UCL (University College London).

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Abstract

Critical size bone defects after fracture or malignant tumour resection are still a challenge to repair in orthopaedics. Stem cell therapy combined with cytokines and bone grafts has the potential to improve outcomes. However, this application has its drawbacks preventing it from popular clinical use. The large number of stem cells required for transplantation is often a limiting factor. The goal of this thesis was to make the stem cells more effective and efficient in bone repair thus potentially reducing the required number of cells. In this study I engineered stem cells by the introduction of a gene to over express stromal cellderived factor-1 (SDF-1), a pivotal chemokine that has been proved to regulate cell migration, with the hypothesis that these cells would effectively increase the migration of native cells to the site of the repair, thus, enhancing bone repair. In vitro treatment of recombinant SDF-1 to human mesenchymal stem cells induced significantly greater osteogenic differentiation compared with control cells (p=0.024) and increased the migration of non-infected cells in a trans-well migration test (p=0.04). In a rat femoral bone defect model, using a low number of bone marrow cells, resulted in no difference in bone formation compared control defects without cells. Interestingly, the same number of bone marrow cells overexpressing SDF-1 showed significantly (86% increase, p=0.02) more new bone formation within the gap and less bone mineral loss at the area adjacent to the defect site during the early bone healing stage. A greater number of donor cells transfected with SDF-1 remained in the repair site compared with the control non-transfected site. An additional second cell injection of cells at 3 weeks was applied to the fracture but did not result in increased new bone formation but did reduce bone mineral loss at this time point. This thesis demonstrates that by applying stem cells transfected with SDF-1, bone fracture healing was improved using a low cell number, which is a non-optimal condition for normal stem cell transplantation. This suggests that SDF-1 transfected cells recruited more host’s stem cells into the fracture gap or resulted in greater osteogenic differentiation, preventing bone loss and increasing bone formation. These findings need further investigations to reveal the mechanism of SDF-1 in bone healing by studying the effects of down stream signaling pathway of SDF-1, the cell type of the recruited cells and the angiogenesis in the defect site.

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