Bone marrow-derived progenitor cell populations have been implicated in tissue regeneration and also in human disease pathology. This thesis investigated the hypothesis that Clara Cell Secretory Protein positive (CCSP+) epithelial-like progenitor cells and circulating fibrocyte numbers are altered in human lung disease and injury, and aimed to determine the predictive value of these cell profiles. It was found that cystic fibrosis patients have an increased number of CCSP+ cells in their bone marrow and peripheral blood, while patients with bronchiolitis obliterans syndrome (BOS) have a decreased number. In addition, BOS and pulmonary fibrosis patients have increased circulating fibrocytes. In response to ischemia reperfusion injury, an increase in CCSP+ cells in the peripheral blood was found at 24 hrs following lung transplant. Lastly, in patients studied greater than 1-year from transplant, those diagnosed with BOS had a higher number of fibrocytes and a loss of CCSP+ peripheral blood cells when compared to patients with stable lung function, with increased fibrocytes being associated with time post-transplant. In these patients, the ratio of fibrocytes-to-CCSP+ cells was predictive of lung function.
Multiplex protein arrays were used to investigate corresponding patient plasma, aiming to elucidate key mediators of progenitor cell recruitment. While differences in various cytokines were found between end-stage diseases, a specific relationship between Stem Cell Growth Factor- and CCSP+ cells was identified and between Monocyte Chemotactic Protein-1 and fibrocytes. Conversely, response of CCSP+ cells following transplant appears to be mediated by known mobilizing factors SDF-1 and GM-CSF. Interestingly, in patients followed long-term after transplant, MCP-1 was associated with the number of CCSP+ cells, while SDF-1 correlated with fibrocyte numbers. These observations suggest common pathways acting on both populations that may be altered by the microenvironment, and may further suggest a common origin. This work contributes important information regarding changes in lung progenitor cells and their association with human disease and tissue repair, which could ultimately support future directions that directly advance therapy and improve patient care.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32068 |
| Date | 19 January 2012 |
| Creators | Gilpin, Sarah Elizabeth |
| Contributors | Waddell, Thomas K. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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