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

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.

  • Strunz, M.
  • Simon, L. M.
  • Ansari, M.
  • Kathiriya, J. J.
  • Angelidis, I.
  • Mayr, C. H.
  • Tsidiridis, G.
  • Lange, M.
  • Mattner, L. F.
  • Yee, M.
  • Ogar, P.
  • Sengupta, A.
  • Kukhtevich, I.
  • Schneider, R.
  • Zhao, Z.
  • Voss, C.
  • Stoeger, T.
  • Neumann, J. H. L.
  • Hilgendorff, A.
  • Behr, J.
  • O'Reilly, M.
  • Lehmann, M.
  • Burgstaller, G.
  • Konigshoff, M.
  • Chapman, H. A.
  • Theis, F. J.
  • Schiller, H. B.

Keywords

  • Alveolar Epithelial Cells/cytology/*metabolism
  • Animals
  • Cell Communication
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Humans
  • Keratin-8/genetics/*metabolism
  • Lung Injury/chemically induced/metabolism/pathology
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Alveoli/cytology/*physiology
  • Pulmonary Fibrosis/metabolism/*pathology
  • *Regeneration
  • Single-Cell Analysis
  • Stem Cells/cytology/*metabolism
Publication details
DOI: 10.1038/s41467-020-17358-3
Journal: Nat Commun
Pages: 3559
Number: 1
Work Type: Original
Access number: 32678092
See publication on PubMed
chevron-down