Associate Professor University of Nottingham Nottingham, United Kingdom
Abstract: Lung alveoli are comprised of two epithelial cell types; Type I alveolar epithelial cells (AT1s) that facilitate gas exchange, and type II alveolar epithelial cells (AT2s), a progenitor cell that secretes pulmonary surfactant and is responsible for alveolar homeostasis and wound repair. In response to normal cell turnover, AT2s can self-renew, or differentiate in AT1s to restore normal epithelial cell composition. In response to acute injury, AT2s also have the capacity to dedifferentiate into basal cells to facilitate more wide-spread tissue repair. Alveolar regeneration and repair is a tightly controlled process involving interactions with stromal, endothelial and immune cells. During chronic injury, mechanisms of alveolar wound repair can become dysregulated leading to the appearance of aberrant basaloid cells, myofibroblasts and pro-inflammatory immune cells that collectively cause inflammation, fibrosis and a failure to re-establish normal alveolar epithelial composition and architecture resulting in functional decline. The mechanisms driving this dysregulated wound healing are not well understood. Here we have developed hIPSC-derived immune competent alveolar organoids that contain AT2s, macrophages, fibroblasts, endothelial and dendritic cells to better understand mechanisms of normal and pathogenic wound healing. Using scRNA-seq and models representative of normal homeostasis, acute (particulate matter exposure) and chronic (pulmonary fibrosis) injury we identify signatures of normal and pathogenic wound healing, including the production of basal cells, myofibroblasts, M1 & M2 polarised macrophages and rare aberrant basaloid cells. These different cell types appear in an injury dependant manner, confirmed via mapping to the human lung cell atlas, reflecting known repair mechanisms in the lung, as well as associated gene expression, cell-signalling and inflammatory cytokine profiles. Additional analysis such as cell-cell interactions and disease ontology further confirm that our models replicate alveolar disease and wound repair. Our approach provide new opportunities to understand mechanisms driving normal and pathogenic wound repair and identify novel interventions that may reduce the impact of respiratory disease.
