Medicine (Northwest Academic Centre) - Theses
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ItemThe biological characterization of circulating osteoprogenitor cells and their role in geriatric musculoskeletal disease( 2021)Circulating Osteoprogenitor (COP) cells are a relatively newly identified population of musculoskeletal precursor cells in the peripheral circulation. While some evidence has shown their capacity for osteogenic differentiation, there is little else known. Additionally, there is contradiction between studies regarding their origin – whether from the mesenchymal, or hematopoietic lineages. Research into COP cells, particularly the hematopoietic lineage, has been slowed by the lack of ability for isolation and expansion in culture – limiting understanding of their potential for use clinically. In this thesis, a model for the isolation, and expansion of COP cells is designed and validated. COP cells expressing CD45, CD34, and alkaline phosphatase can be isolated through flow cytometric cell sorting and proliferate in culture. They are also able to form bone in vitro. This is followed by a detailed -omics scale characterization of the cells, utilizing transcriptomic and proteomic approaches. This analysis found that they are a distinct cell population, with characteristics of both mesenchymal progenitors and immune cells. They show significant transcriptomic and proteomic overlap with mesenchymal stem cells and adipose-derived stem cells, expressing a range of genes and proteins associated with differentiation and proliferation. They also show several changes associated with aging, such as decreased protein translation, vesicular transport and cell cycle regulation, and increased proteins associated with ion homeostasis and transport. While regulated in aging, there were no changes in COP cell physiology with sex difference, at the genetic or proteomic level. Finally, to aid clinical translation in the management of chronic musculoskeletal disease, two clinical studies are described. One, a cross-sectional analysis, identifies correlations with important musculoskeletal parameters such as bone mineral density and content and evaluates their value as a biomarker of osteoporosis. It shows that COP cells are strongly associated with bone mineral density, particularly of the neck of the femur. COP cells are also associated with male sex and appendicular lean mass. Importantly, the percentage of COP cells in the circulation shows good performance as a biomarker of osteoporosis of the neck of the femur and total body. The second study, an interventional study examines the effect of vitamin D supplementation on COP cell numbers. It shows that supplementation with vitamin D leads to an increase in the percentage of COP cells in the circulation.