Fibroblast-mediated resolution of basal metaplasia in lung fibrosis

Project Summary/Abstract One of the hallmarks of severe fibrotic injuries of the lung is the appearance of metaplastic airway basal cells in the damaged alveoli. In patients with idiopathic pulmonary fibrosis (IPF), this pathognomonic feature is described as “bronchiolization,” which denotes the appearance of bronchus-like structures in the scarred alveoli that leads to cystic remodeling in the lung. In this proposal, we seek to define pro-reparative differentiation pathways in both the fibroblast and stem cell compartment that can be leveraged as therapy. Our preliminary data demonstrated the appearance of an alveolar fibroblast population during fibrotic injury resolution in mouse that expresses the extracellular hedgehog antagonist, HHIP, concurrent with a metaplastic basal cell-to-alveolar type 2 (AT2) cell differentiation trajectory in the alveoli undergoing repair. Furthermore, we generated a chimeric HHIP protein that demonstrated efficacy in promoting basal-to-AT2 differentiation in vivo. Utilizing a combination of novel genetic tools to trace and delete HHIP+ fibroblasts, xenotransplant model of human metaplastic basal cells, and a novel pharmacologic reagent made in our lab to target metaplastic basal cell differentiation, this proposal will test the central hypothesis that HHIP+ alveolar fibroblasts emerge after fibrotic injury to promote the restoration of alveolar progenitors from metaplastic basal cells. Finally, we will determine whether HHIP can be leveraged as pharmacotherapy to reverse pathogenic remodeling seen in IPF, and establish a humanized preclinical model to test the effect of therapeutics to reverse metaplastic remodeling in the fibrotic alveoli. Successful completion of this proposal will define a stem cell lineage trajectory that leads to reversal of remodeling seen in IPF, and provide preclinical studies to validate this therapeutic strategy.