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<p>Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons 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 (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 10<sup>10</sup> iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Heřmanský–Pudlák Syndrome 1 (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.</p>

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Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis

  • 期刊论文

  • 发表日期：

    2025年2月24日

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  • Mikael G. Pezet,
  • Juan A. Torres,
  • Tania A. Thimraj,
  • Ivana Matkovic,
  • Nadine Schrode,
  • John W. Murray,
  • Anjali Saqi,
  • Kristin G. Beaumont,
  • Hans-Willem Snoeck

摘要

Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons 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 (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 1010 iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Heřmanský–Pudlák Syndrome 1 (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.