Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPSCs

Respir Res. 2021 Nov 4;22(1):284. doi: 10.1186/s12931-021-01877-8.


Background: Somatic cells differentiated from patient-specific human induced pluripotent stem cells (iPSCs) could be a useful tool in human cell-based disease research. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive genetic disorder characterized by oculocutaneous albinism and a platelet dysfunction. HPS patients often suffer from lethal HPS associated interstitial pneumonia (HPSIP). Lung transplantation has been the only treatment for HPSIP. Lysosome-related organelles are impaired in HPS, thereby disrupting alveolar type 2 (AT2) cells with lamellar bodies. HPSIP lungs are characterized by enlarged lamellar bodies. Despite species differences between human and mouse in HPSIP, most studies have been conducted in mice since culturing human AT2 cells is difficult.

Methods: We generated patient-specific iPSCs from patient-derived fibroblasts with the most common bi-allelic variant, c.1472_1487dup16, in HPS1 for modeling severe phenotypes of HPSIP. We then corrected the variant of patient-specific iPSCs using CRISPR-based microhomology-mediated end joining to obtain isogenic controls. The iPSCs were then differentiated into lung epithelial cells using two different lung organoid models, lung bud organoids (LBOs) and alveolar organoids (AOs), and explored the phenotypes contributing to the pathogenesis of HPSIP using transcriptomic and proteomic analyses.

Results: The LBOs derived from patient-specific iPSCs successfully recapitulated the abnormalities in morphology and size. Proteomic analysis of AOs involving iPSC-derived AT2 cells and primary lung fibroblasts revealed mitochondrial dysfunction in HPS1 patient-specific alveolar epithelial cells. Further, giant lamellar bodies were recapitulated in patient-specific AT2 cells.

Conclusions: The HPS1 patient-specific iPSCs and their gene-corrected counterparts generated in this study could be a new research tool for understanding the pathogenesis of HPSIP caused by HPS1 deficiency in humans.

Keywords: Alveolar epithelial type 2 cells; Giant lamellar body; HPS1; Patient-specific iPSCs.

MeSH terms

  • Alveolar Epithelial Cells / pathology*
  • Animals
  • Cells, Cultured
  • DNA / genetics*
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Hermanski-Pudlak Syndrome / genetics*
  • Hermanski-Pudlak Syndrome / pathology
  • Humans
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mutation*
  • Phenotype
  • Proteomics / methods*


  • HPS1 protein, human
  • Membrane Proteins
  • DNA