Molecular Mechanisms of Mucociliary Epithelia and Airway Clearance
Cell Biology
Final Report Abstract
Mucociliary epithelia are important for animal development and human health, e.g. through providing mucociliary clearance to remove pathogens and prevent infections of the lung. Secretory cells secrete mucus and antimicrobial peptides, while ciliated cells drive fluid flow and removal of mucus and pathogens from the tissue, and basal cells act as stem cells of the epithelium during homeostasis and regeneration. In chronic airway diseases, changes in tissue composition (loss of ciliated cells, increase in secretory cells or accumulation of stem cells without differentiation) lead to dysfunction of mucociliary clearance, but the underlying molecular mechanisms are not sufficiently understood to provide a early diagnosis and effective treatments for patients. This project aimed at gaining a better understanding of the signals and cell processes that control normal development and regeneration of cell types and cilia function to elucidate the molecular cascades that lead to disease related changes in mucociliary function and to identify potential therapeutic entry points. Result from this project identified the molecular and genetic processes underlying basal cell hyperplasia, a precancerous condition of the airways, of goblet metaplasia, associated with asthma and chronic obstructive pulmonary disease, as well as novel routs to interconnect both phenotypes in vertebrates. These changes were driven largely by dysregulated Wnt and Notch signaling affecting the expression of key transcription factors involved in stem cell and secretory cell regulation. Furthermore, we identified potential intervention strategies for these conditions, making our findings highly translationally relevant. Furthermore, we established in this work a novel model to study patient-derived cells in or ganoid cultures, a novel model to study tissue remodeling and loss of ciliated cells in vivo, and methods to study dynamic developmental gene expression and cell type compositions in mucociliary epithelia. In partially still unpublished work, we have further identified how different subtypes of secretory cells with specific secretory profiles are specified, which Wnt ligands and receptors regulate aspects of mucociliary development and now Notch signaling is integrated in the regulation of basal stem cells. Together, this project has revealed new molecular and developmental mechanisms controlling ciliation and cell types of mucociliary epithelia and provided the basis for a better understanding of ciliopathies and chronic lung diseases in humans.
