Synovial Stem Cell Biology

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Articular cartilage does not exhibit endogenous repair, in part because of a lack of stem/progenitor cells in the tissue, whereas the adjacent synovial membrane is abundant with mesenchymal stem cells (MSCs) capable of differentiating into cartilage both in vitro and in vivo. We have demonstrated that the MSCs within the joint are very sensitive to changes in the micro-environment and that changes in the synovial fluid can regulate the chondrogenic potential of the cells. In addition, we have also found that MSCs from injured/arthritic/inflamed joints are incapable of fully differentiating into chondrocytes under specific culturing conditions whereas MSCs from normal joints are fully functional. We have explored this effect in great depth and found evidence that suggests CCL2/MCP-1 is being secreted from synovial macrophages and now have preliminary evidence that these macrophage cells may be acting as a synovial stem cell niche. The stem cell niche is hypothesized to provide a micro-environment that is capable of directing stem cell activity. The niche is thought to be particularly important in regards to the decline of stem cell activity with aging, in which a loss of tissue homeostasis progresses as the resident stem cell populations prove to be increasingly inadequate in terms of maintenance and repair. However, in vitro evidence demonstrates that these stem cells when separated from the niche are still functional, strongly suggesting that the stem cell niche maybe failing during aging and disease processes. The objective of my program is to elucidate the regulatory feedback mechanisms that exist between macrophages and synovial MSCs within human and mouse knee joint synovium and understand how these pathways regulate stem cell fate in vitro, ex vivo and in vivo. This will be achieved by undertaking the following aims: Aim 1 (In vitro): Determine which signaling molecules produced by macrophages regulate synovial MSCs, and assay if this ability is augmented through modification of the macrophage activation state. Aim 2 (Ex vivo): Assay for changes in synovial MSC function when macrophages are removed from the synovium using a targeted liposomal based approach. Aim 3 (In vivo): Quantify changes in synovial MSC mediated tissue repair when macrophage number or activation state is experimentally modified within the synovial stem cell niche. This program of research will result in significant advances in the field of cell biology and bioengineering by contributing to i) the understanding of the role of macrophages in the synovial stem cell niche including how these cell regulate stem cell potential; and ii) a framework for the potential development of new and improved tissue engineering / regenerative medicine approaches to restoring and/or maintaining normal joint function with aging or after injury.