PROGENITOR CELLS OF THE ADULT HUMAN AIRWAY INVOLVED IN SUBMUCOSAL GLAND DEVELOPMENT

A bronchial xenograft model of the human airway was used to identify s ubmucosal gland progenitor cells within the surface airway epithelium. Lineage analysis using recombinant retroviruses has demonstrated cons iderable diversity in the cellular composition of expanded clones with in reconstituted xenograft airway epithelium. These findings provide e vidence for the existence of multiple progenitors in the airway with e ither limited or pluripotent capacity for differentiation. Furthermore , the development of transgene-expressing submucosal glands was associ ated with a single subset of surface airway epithelial clones. This gl and progenitor cell demonstrated two discernible characteristics consi stent with the identification of an airway stem cell including: (1) pl uripotent capacity for airway differentiation and (2) a two-fold highe r proliferative rate than other observed clone types. The number of pr ogenitor cells involved in gland development was also assessed by clon al analysis using alkaline phosphatase and beta-galactosidase transgen es. These studies demonstrated that more than one airway progenitor ce ll is involved in the initial stages of gland development. A second ex planation for the high prevalence of non-clonality in developing gland s was suggested from three-dimensional reconstruction of transgene mar ked glands. These reconstruction experiments demonstrated that 27% of glands contained more than one duct to the surface airway epithelium. This observation suggests a novel mechanism of gland morphogenesis by which independently formed glands interact to join glandular lumens. S uch a mechanism of glandular development and morphogenesis may play an important role in normal submucosal gland development and/or the prog ression of hypersecretory diseases of the adult human airway as seen i n cystic fibrosis, chronic bronchitis and asthma. The identification o f progenitor cells with the capacity to form submucosal glands has imp lications on the targets for gene therapy in cystic fibrosis.