| The elucidation of mechanisms for epithelial maintenance and renewal after injury are central to understanding aspects of normal airway diversity and the pathobiology of lung diseases including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cancer. Due to the low steady state turnover of the airway epithelium, it has been proposed that epithelial remodeling following chronic lung injury or disease may be the result of aberrant epithelial stem cell activation. Previous results indicated that intrapulmonary conducting airways contain rare populations of stem cells that localized to neuroepithelial body (NEB) microenvironments, and that these cells are activated following injury involving depletion of airway Clara cells. These airway cells were uniquely pollutant resistant, exhibited robust mitotic and differentiation potential, and exhibited the molecular property of Clara cell secretory protein (CCSP) expression. Despite this recent progress, many aspects of airway stem cell maintenance, initiation, and regulation remain elusive.; Studies presented in this dissertation were undertaken (1) to investigate the existence of alternate, regionally distinct airway stem cell populations, (2) to elucidate mechanisms of airway stem cell pollutant resistance, and (3) to identify signaling pathways associated with stem cell-associated repair. Results of these studies demonstrate the existence of unique, NEB microenvironment-independent CCSP expressing stem cells restricted to airway bronchoalveolar duct junction (BADJ) microenvironments. Results also identify likely mechanisms of CCSP expressing stem cell pollutant resistance that include reduced levels of Cytochrome P450 expression and robust drug/pollutant efflux systems. Finally, results of these studies indicate that activation of the beta-catenin signaling pathway and definitive downstream target genes occurs within NEB and BADJ microenvironments during airway regeneration. Together, these findings demonstrate that regionally distinct, pollutant resistant airway stem cell populations are responsible for the maintenance of appropriate epithelial diversity and facilitate renewal processes after injury. Furthermore, these studies support the notion that beta-catenin signaling and downstream target gene activation are important mediators of stem cell-associated epithelial renewal. |
