YAP/TAZ as crucial regulators of lung progenitor cell fate and epithelial-mesenchymal homeostasis

Abstract

The adult murine respiratory system contains several stem and progenitor cells that, under homeostatic conditions, slowly self-renew and give rise to multiple lung lineages. Upon injury, however, these stem and progenitor cells undergo rapid expansion and gain cellular plasticity. In this thesis, I set out to investigate the role of YAP/TAZ activity on cell fate decision of Club cell, a lung facultative stem cells in adult murine lung. To do this, Club cell was depleted of core Hippo pathway kinases Lats1 and Lats2 and its lineage was traced with tdTomato labeling.Deletion of Lats1 and Lats2 in Club cells resulted in bronchial epithelial dysplasia, causing non- transformed bronchial epithelial cells to detach from the epithelial layer and slough into the airway lumen. The majority of lineage labelled Lats1/2-depleted cells flattened and expressed classical markers of alveolar type Icells (ATI). Previous studies demonstrated the role of YAP to be de-differentiation into basal stem cell in adult tracheal Club cell, and differentiation into ATI cell during developmental stage. However, this study demonstrates that activation of YAP/TAZ in both adult bronchial Club cell and developing epithelial cell induces strong trans- differentiation into ATI cell. I also show that during the course of the differentiation, Club cell passes through DATP-like cell, but not alveolar type II (ATII) cell. Also, the activation of YAP/TAZ in Club cell results in paracrine accumulation of neighboring collagen and proliferating mesenchymal cells. These cell fate conversion and disruption in neighboring mesenchyme are shown to associate with amino acid availability and mTOR activity.In summary, this thesis shows a novel Club-DATP-like-ATI cell differentiation trajectory and perturbed epithelial-mesenchymal homeostasis in response to YAP/TAZ activation in Club progenitor cell. It also shows the involvement of amino acid and mTOR activity during those two outcomes.