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

Nature communications (2020-07-18)
Maximilian Strunz, Lukas M Simon, Meshal Ansari, Jaymin J Kathiriya, Ilias Angelidis, Christoph H Mayr, George Tsidiridis, Marius Lange, Laura F Mattner, Min Yee, Paulina Ogar, Arunima Sengupta, Igor Kukhtevich, Robert Schneider, Zhongming Zhao, Carola Voss, Tobias Stoeger, Jens H L Neumann, Anne Hilgendorff, Jürgen Behr, Michael O'Reilly, Mareike Lehmann, Gerald Burgstaller, Melanie Königshoff, Harold A Chapman, Fabian J Theis, Herbert B Schiller
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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