Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis

Abstract

Stem cells undergo dynamic changes in response to injury to regenerate lost cells. However, the identity of transitional states and the mechanisms that drive their trajectories remain understudied. Using lung organoids, multiple in vivo repair models, single-cell transcriptomics, and lineage tracing, we find that alveolar type-2 epithelial cells undergoing differentiation into type-1 cells acquire pre-alveolar type-1 transitional cell state (PATS) en route to terminal maturation. Transitional cells undergo extensive stretching during differentiation, making them vulnerable to DNA damage. PATS show an enrichment of TP53, TGFβ, DNA-damage response signalling, and cellular senescence. Gain and loss of function and genomic binding assays revealed a direct transcriptional control of PATS by TP53 signalling. Notably, PATS-like cells were accumulated in human fibrotic lungs, suggesting persistence of the transitional state in fibrosis. Our study thus

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

“…A recent study reported a cluster of lung alveolar epithelial cells called pre-alveolar type-1 transitional state (PATS) represent cells at transitional stage from AEC2 to AEC1 (Kobayashi et al, 2020). PATS cells highly express CLDN4 and they emerge after injury in mouse lung and are enriched in IPF lung (Kobayashi et al, 2020). In our study, we found that Cldn4 only expressed in subset AEC2-3 cells in injured mouse lung and CLDN4 expression is elevated in AEC2s from IPF lung.…”

“…This result indicate that our subset classification of AEC2s with mouse model is bioogicaly relevant to human disease. A recent study reported a cluster of lung alveolar epithelial cells called pre-alveolar type-1 transitional state (PATS) represent cells at transitional stage from AEC2 to AEC1 (Kobayashi et al, 2020). PATS cells highly express CLDN4 and they emerge after injury in mouse lung and are enriched in IPF lung (Kobayashi et al, 2020).…”

“…Both claudins (Kage et al, 2014) and keratins are tight junction proteins and the markers of epithelial differentiation. Recent reports suggest Krt8+ or Krt19+ AEC2s are progenitor cells in a transitional state from AEC2 to AEC1 in the lung (Kobayashi et al, 2020;Strunz et al, 2020). Much detailed lineage tracing studies and the progenitor characterization especially in IPF are needed to confirm the role of this subpopulation in lung repair.…”

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

“…Recent work, using mouse AT2 cell organoids, has elucidated a developmental trajectory by which AT2 cells can differentiate via an intermediate state into type I alveolar epithelial (AT1) cells in response to bleomycin injury (Choi et al, 2020;Kobayashi et al, 2020;Strunz et al, 2020). Of note, the intermediate cells are characterized by high levels of p53 signaling and DNA damage which resolves with their final transition to an AT1 cell fate (Kobayashi et al, 2020), arguing that repairing DNA damage, potentially at telomeres, is an important step in the transition to an AT1 cell.…”

Reproducible Single-Cell Genomic Research in Pulmonary and Critical Care Medicine

“…Specifically, single-cell RNA-seq has been applied to create reference atlases of normal human lung tissue (3-6), to study cellular cross-talk in multicellular lung cancer niches (7,8), to discover novel cell types in the normal lung (9) or in pulmonary fibrosis (10)(11)(12)(13)(14)(15)(16), to evaluate remodeling of the airway epithelium in asthma (17) or as a result of smoking (18), to study the immune response in cystic fibrosis (19), and in COVID-19 (20)(21)(22). By applying the power of single-cell techniques to causal experiments in model organisms or in vitro systems, investigators were able to provide mechanistic insights about the role of specific cell types to disease pathogenesis (23)(24)(25).…”