2026 Theses Doctoral

Modeling Idiopathic Pulmonary Fibrosis Using Human Pluripotent Stem Cell-Derived Induced Respiratory Airway Progenitors

Torres, Juan Antonio

The human lung differs substantially from rodent lungs, yet mouse models remain standard in pulmonary research. Findings in murine models helped give rise to the prevailing theory that AT2 cells are the primary regenerative cell of the alveolus, capable of self-renewal and of generating the flat AT1 cells that help mediate gas exchange. AT2 cell dysfunction is also thought to drive idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease with no curative treatment besides lung transplantation. A distinct feature of IPF is the accumulation of KRT17+/KRT5- aberrant basaloid cells (aBCs).

Rodents, however, lack terminal respiratory bronchioles (TRBs), the final branches of the bronchiolar tree, and their associated resident cells. Thus, it is unknown whether TRB-associated cells play a role in IPF pathogenesis. Here, we develop a human pluripotent stem cell-derived model for TRBCs, and show their capacity for differentiation into AT1 cells. IPF-associated mutations impair this differentiation, directly implicating TRBCs in IPF pathogenesis. We also characterize a KRT17+ aBC and aBC-like population, distinguishing true pathogenic aBCs from transient aBC-like intermediates in the TRBC-to-AT1 cell differentiation pathway. We find that existing fibrosis mouse models do not recapitulate pathogenic aBCs. Finally, we conclude that in humans, AT2-to-AT1 differentiation is unlikely to be the primary route of alveolar regeneration. Together, this work argues that distal airway cells are primary progenitors for alveolar regeneration in humans, and that their dysfunction is a critical driver of IPF.