Sanghani-Kerai, Anita; (2018) Do stem cells transfected with CXCR4 enhance bone formation in osteoporosis? Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Osteoporosis affects bone mass and bone micro-architecture, reducing mechanical strength. SDF-1 and its ligand CXCR4 play significant roles in the migration and engraftment of mesenchymal stem cells (MSCs). The aim of this study was to investigate the effects of CXCR4 transfected MSCs on bone formation in osteopenic rats. The hypothesis was that MSCs genetically modified to over-express CXCR4, would enhance migration of stem cells from osteopenic rats and when injected intravenously in ovariectomised (OVX) rats, would improve bone formation. MSCs were harvested from femora of young, OVX and adult control rats. The differentiation, CXCR4 expression, in vitro migration and phenotypic characteristics of the cells were compared. Although the phenotypic characteristics of cells from all groups of rats were the same, their differentiation capability, CXCR4 expression and migration was significantly different. MSCs were genetically modified to over-express CXCR4 and in vitro migration investigated. It was found that although young MSCs had the highest migration capability (2x more than their uninfected counterparts, p=0.006), the OVX MSCs when transfected with CXCR4 had the most significant migration from their un-transfected counterpart cells(5x more, p=0.025). Additionally, differentiating MSCs to osteoblasts reduced their CXCR4 expression as well as their migration towards SDF1. The CXCR4 transfected MSCs were administered intravenously in OVX rats. Fluorescent labelled cells were tracked after 1 week and were located in the blood vessels of the femur. 11-weeks post-injection, OVX rats injected with young-CXCR4 MSCs had significantly higher BMD(694.0±80.1mg/cm3) (p<0.05) in comparison to rats injected with saline. Rats injected with OVX-CXCR4 MSCs(645.4±79.3mg/ccm) had a higher BMD in comparison to those injected with OVX MSCs(631.4±69.5mg/ccm) and saline(563.4±82.9mg/ccm). The L4 vertebral stiffness was also higher in rats treated with young-CXCR4 MSCs in comparison to those treated with saline. CXCR4 genetically modified MSCs from young and OVX patients may help in boosting bone formation in osteoporosis.

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