Generation of expandable multipotential distal lung progenitors from human pluripotent stem cells that model idiopathic pulmonary fibrosis [scRNA-Seq]
Human lungs contain unique cell populations in distal respiratory airways and terminal bronchioles (RA/TRB) that accumulate in patients with lung injury and idiopathic pulmonary fibrosis (IPF), a lethal lung disease. As these populations are absent in rodents, deeper understanding requires a human in vitro model. Here we convert human pluripotent stem cells into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of  ~99% RA/TRB-associated cell types. One hPSC can give rise to 1010 iRAP cells. We differentiate iRAPs through a stage consistent with transitional AT2 like cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of HPS1, which causes pulmonary fibrosis in humans, replicate the aberrant differentiation and recruitment of profibrotic fibroblasts observed in IPF, indicating that intrinsic dysfunction of RA/TRB-associated alveolar progenitors contributes to HPS1-related IPF. iRAPs may provide a system suitable for IPF drug discovery and validation. Overall design: We performed single cell RNA sequencing on iRAPs, iAT1 and transitional type 2 alveolar epithelial. The samples were dissociated to single cells and resuspended at a concentration of 5000 cells/ul for sequencing.