IPF AT2 cells are stuck in transition and biophysically dysfunctional

Abstract Idiopathic Pulmonary Fibrosis (IPF) is an incurable disease with extensive molecular, cellular, and organ level dysfunction. A major gap in IPF research is the lack of understanding of how short-term cellular behavior causes long-term tissue remodeling. By optimizing lung slices from explanted human lungs, we discovered foci of migratory non-canonical alveolar type 2 (AT2) cells in regions of established lung fibrosis and found that these cells are trapped in states of cellular transition that are driven by persistent developmental repair programs. Consistent with these biophysical behaviors, pharmacological activation of β-catenin reproduced persistent migration, whereas YAP activation restrained it. We conclude that imbalanced developmental programs drive AT2 cell motility and lesion heterogeneity, providing a mechanistic link between short-term cellular dynamics and slowly progressive fibrosis of IPF. Competing Interest Statement The authors declare the following competing interests: DAS is the founder and chief scientific officer of Eleven P15, Inc., a company dedicated to the early diagnosis and treatment of pulmonary fibrosis. ITS, RZB, IVY and CDC are Consultants for Eleven P15, Inc. The remaining authors declare no competing interests.