Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

Nat Commun. 2020 Jul 16;11(1):3559. doi: 10.1038/s41467-020-17358-3.

Abstract

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / cytology
  • Alveolar Epithelial Cells / metabolism*
  • Animals
  • Cell Communication
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Humans
  • Keratin-8 / genetics
  • Keratin-8 / metabolism*
  • Lung Injury / chemically induced
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / physiology*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Regeneration*
  • Single-Cell Analysis
  • Stem Cells / cytology
  • Stem Cells / metabolism*

Substances

  • KRT8 protein, human
  • Keratin-8