Aberrant epithelial reprogramming can take the form of metaplasia, characterized by the appearance of mature cell types that are not normally present at the site of injury. In organ fibrosis, this often culminates in a transformed barrier composed of matrix-laden scars and metaplastic epithelium. A pathognomonic feature of idiopathic pulmonary fibrosis (IPF) is the ectopic appearance of KRT5+ basal cells in the damaged alveolar compartment, the presence of which correlates with disease severity and survival. This suggests that metaplasia is a clinically relevant feature of lung fibrosis, and understanding this pathologic form of epithelial plasticity could present potential therapeutic targets. We have previously shown that hedgehog (Hh)-activated mesenchyme contributes to components of the scar in fibrotic repair. We now demonstrate that Hh-activated mesenchyme functionally interacts with airway progenitors to promote metaplastic KRT5 differentiation in the fibrotic lung. Furthermore, we show that a Hh-BMP signaling circuit in the airway progenitor niche regulates the metaplastic outcome during fibrotic repair. Our central hypothesis is that mesenchymal Hh activation upregulates BMP antagonists in the progenitor niche, which drives epithelial metaplasia in both human and mouse lungs, and this Hh-BMP circuit can be targeted to mitigate and reverse metaplasia in lung fibrosis. Leveraging novel genetic/pharmacologic tools we have developed, our single and bulk RNAseq bioinformatics capacity, and our access to human samples, this proposal aims to address how the mesenchymal compartment of the progenitor niche modifies epithelial plasticity in fibrotic repair, and outlines a potential pre-clinical pipeline to identify compounds that can target epithelial metaplasia in lung fibrosis.
Efforts to treat Idiopathic pulmonary fibrosis (IPF), the most common and deadly form of a large group of lung fibrotic diseases, have mostly targeted the scarring process. However, IPF is also characterized by the appearance of abnormal stem cell populations in areas of damage, a process known as metaplasia. The studies outlined in this proposal will test the idea that metaplasia can alter lung function in fibrotic diseases, and develop a pre-clinical pipeline to test therapies that can target metaplasia in patients with IPF.
