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

  • Author(s): Strunz, Maximilian;
  • Simon, Lukas M;
  • Ansari, Meshal;
  • Kathiriya, Jaymin J;
  • Angelidis, Ilias;
  • Mayr, Christoph H;
  • Tsidiridis, George;
  • Lange, Marius;
  • Mattner, Laura F;
  • Yee, Min;
  • Ogar, Paulina;
  • Sengupta, Arunima;
  • Kukhtevich, Igor;
  • Schneider, Robert;
  • Zhao, Zhongming;
  • Voss, Carola;
  • Stoeger, Tobias;
  • Neumann, Jens HL;
  • Hilgendorff, Anne;
  • Behr, Jürgen;
  • O'Reilly, Michael;
  • Lehmann, Mareike;
  • Burgstaller, Gerald;
  • Königshoff, Melanie;
  • Chapman, Harold A;
  • Theis, Fabian J;
  • Schiller, Herbert B
  • et al.
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.

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