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