Role of repair supportive mesenchymal cells (RSMCs) in airway epithelial regeneration

The conducting airways of the respiratory system harbor specialized populations of epithelial progenitor cells that are employed to promote regeneration upon injury. On the other hand, the microenvironment that hosts these cells is populated by mesenchymal niche cells that closely communicate with epithelial cells, often reviving developmental pathways and mechanisms in this process. Here, we deconvoluted the mesenchymal complexity to establish a genetic signature for repair-supportive mesenchymal cells (RSMCs), a novel niche population that is distinct from airway smooth muscle cells (ASMCs) and investigated the mode of action of these cells in relation to paracrine communication with epithelial progenitor cells. Using a combination of genetic lineage tracing, single-cell transcriptomics, histology, and ex vivo models including murine and human airway organoids, we found that RSMCs derive from adventitial rather than peribronchial fibroblasts. These cells secrete WNT signaling inhibitors that target airway epithelial cells to promote epithelial regeneration. We also demonstrate that these findings are clinically relevant in the context of airway disease associated with chronic obstructive pulmonary disease (COPD).