Generation of expandable multipotential distal lung progenitors from human pluripotent stem cells that model idiopathic pulmonary fibrosis [bulk RNA-Seq]

Human lungs contain distal respiratory airways (RAs) that are absent in rodents and contain unique cell populations that are more abundant in patients with lung injury and idiopathic pulmonary fibrosis (IPF). A deeper understanding of the potential of these cells requires an in vitro model. Here we report the generation from human pluripotent stem cells of expandable spheres ('induced respiratory airway progenitors' (iRAPs)) consisting of RA-associated cell types that could be differentiated into type 1 and type 2 alveolar epithelial cells in defined conditions and show defects that are hallmarks of IPF when mutant for HPS1, a gene associated with IPF in humans. These data indicate that alveolar epithelial cells can derive from distal airway progenitors and that their intrinsic dysfunction may be involved in aberrant, fibrotic repair in IPF. iRAPs thus provide a model to gain insight into human lung regeneration and into pathogenesis of IPF. Overall design: To identify pathways of differentiation, and find association in our alveoloar type 1 model we performed RNA sequencing on transitional AT2-like cells, iRAPs and iAT1 samples.