Longitudinal single cell transcriptomics of lung regeneration reveals a fibrogenesis specific epithelial cell state.

Interactive webtool: Mouse Lung Injury & Regeneration – Schiller & Theis labs @ Helmholtz Center Munich (shinyapps.io)

Link to publication: Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis | Nature Communications

The sequence of transcriptional programs driving stem cell differentiation during lung regeneration has remained elusive. Using longitudinal single cell RNA-seq we resolved cellular processes during mouse lung regeneration for 28 cell types. We found that epithelial stem cells during alveolar regeneration transiently adopt a squamous state that features highly distinct cell-cell communication with mesenchyme and macrophages. Krt8+ alveolar differentiation intermediate (ADI) cells were present exclusively during inflammation and fibrogenesis, lacked canonical markers of alveolar epithelium, and featured highly specific expression of NFkB, p53, N-myc, hypoxia, and Yap/Taz target genes. Using cell state trajectory modeling, guided by RNA velocity of single cells from 18 timepoints and lineage tracing Sox2-CreERT2 and Sftpc-CreERT2 mice, we show that alveolar and airway stem cells converge into Krt8+ ADI cells and delineate gene expression dynamics during this process. More generally, intermediate cell states during tissue repair may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.