Activation of the resident Skeletal Stem Cell (SSC) for articular cartilage regeneration.

The aim of this PhD thesis is to validate that a commonly performed surgical therapy used to treat patients with osteoarthritis (OA), microfracture (MF), can activate tissue-resident Skeletal Stem Cells (SSC) from distal femurs. In Chapter 1 we introduce the topics related to the thesis including; OA overview, stem cell therapies and current stem cell trials used for OA. In Chapter 2 we show that with age there is a reduction in the number of SSC in the articular surface of mouse distal femurs. In Chapter 3 we demonstrate that there is an local, transient activation of SSC following acute MF surgical stimulation. In Chapter 4 we show that augmentation of the niche with growth factors bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor receptor 1 (VEGFR1) following injury results in the regeneration of hyaline-like cartilage. In Chapter 5 we translate our mouse findings in vivo utilising our human xenograft model. In our human xenograft model we confirm that following acute injury there is a similar activation in tissue resident SSC. Niche augmentation with BMP2 and VEGFR1 in the human xenograft model leads to de novo human cartilage formation in a bone niche.