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.
폐 손상 시 재생 과정에서 폐 상피 세포의 변화 양상은 중요한 역할을 한다. 또한, 이 세포는 주위 중간엽 세포와의 상호작용을 통하여 상피-중간엽 세포의 항상성 및 폐 기능 유지에도 중요하다. 하지만, 폐 상피 세포의 변화가 어떻게 조절되는지 정확히 알려진 바 없다. 최근 보고에 따르면 여러 상피 세포 중 클럽 폐 전구세포가 재생 과정과 섬유화증에 중요한 역할을 한다. 본 학위논믄에서는 YAP/TAZ 전사 보조 활성화 인자들이 클럽 폐 전구세포의 변화를 유도한다는 것을 밝혀냈다. 구체적으로, YAP/TAZ 활성화가 일어난 클럽 세포는 DATP-like 세포를 거쳐 제1 폐포세포로 변화한다는 것을 알아냈다. 이 과정에서 일어나는 주변 분비효과로 인해 기관지 주위에 섬유화가 일어나는 것을 관찰했다. 또한, 아미노산의 가용성과 mTOR 신호전달 회로가 이 과정에서 중요하게 작용한다는 것을 밝혀냈다.
