Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease (ILD)
1Boston University, *Corresponding author
Description
Alveolar epithelial type 2 cell (AEC2) dysfunction is implicated in the pathogenesis of adult and pediatric interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF); however, identification of disease-initiating mechanisms has been impeded by inability to access primary AEC2s early on. Here, we present a human in vitro model permitting investigation of epithelial-intrinsic events culminating in AEC2 dysfunction, using patient-specific induced pluripotent stem cells (iPSCs) carrying an AEC2-exclusive disease-associated variant (SFTPCI73T). Comparing syngeneic mutant versus gene-corrected iPSCs after differentiation into AEC2s (iAEC2s), we find that mutant iAEC2s accumulate large amounts of misprocessed and mistrafficked pro-SFTPC protein, similar to in vivo changes, resulting in diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, time-dependent metabolic reprogramming, and nuclear factor κB (NF-κB) pathway activation. Treatment of SFTPCI73T-expressing iAEC2s with hydroxychloroquine, a medication used in pediatric ILD, aggravates the observed perturbations. Thus, iAEC2s provide a patient-specific preclinical platform for modeling the epithelial-intrinsic dysfunction at ILD inception.
Dataset ID
LMEX0000004414
Assay Type
Single-cell RNA-seq
Organism
Human
Stages
Adolescent
Cell Count
7337
Technology
10x Genomics Chromium Single Cell Gene Expression
Reference
Alysandratos et al. (2021)
External databases
GEO: GSE160801
| File | Description | Size |
|---|---|---|
| Gene-signatures.txt | Gene signatures | 21.0K |
| iAEC2-Seurat-barcode-metadata.txt | Seurat barcode metadata | 547.4K |
| iAEC2-metadata.txt | Sample metadata | 493.0B |
| iAEC2-variant-corrected.h5ad | HDF5 annotated format single-cell data matrix | 61.9M |
| pseudobulk_avg_Cell-Type_by_Library.tsv | Expression matrix | 1.0M |
| LungMAP ID | Alt ID | Species | Sex | Race | Age | Age Group |
|---|---|---|---|---|---|---|
| LMSP0000001555 | SPC2 | Homo sapiens | Male | African American | 14 years | Adolescent |