Hae Yon Jeon1,†, Jinwook Choi2,†, Lianne Kraaier2,3, Young Hoon Kim1, David Eisenbarth1, Kijong Yi4,5, Ju-Gyeong Kang1, Jin Woo Kim1, Hyo Sup Shim6, Joo-Hyeon Lee2,7,* & Dae-Sik Lim1,*
1Department of Biological Sciences, National Creative Research Center for Cell Plasticity, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea 2Jeffrey Cheah Biomedical Centre, Wellcome–MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK 3Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands 4Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea 5GenomeInsight Inc., Daejeon, South Korea 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea 7Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
†These authors contributed equally to this work
Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular mechanisms governing these processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells, which subsequently lose their cellular identity and acquire squamous alveolar type 1 (AT1) fate in the lung. This cell fate conversion is mediated via distinctive transitional cell states of damage-associated transient progenitors (DATPs), recently shown to emerge during injury repair in mouse and human lungs. We further describe a YAP/TAZ signaling cascade to be integral for the fate conversion of secretory cells into AT1 fate, by modulating mTORC1/ATF4-mediated amino acid metabolism in vivo. Importantly, we observed aberrant activation of the YAP/TAZ-mTORC1-ATF4 axis in the altered airway epithelium of bronchiolitis obliterans syndrome, including substantial emergence of DATPs and AT1 cells with severe pulmonary fibrosis. Genetic and pharmacologic inhibition of mTORC1 activity suppresses lineage alteration and subepithelial fibrosis driven by YAP/TAZ activation, proposing a potential therapeutic target for human fibrotic lung diseases.