A smooth muscle-like niche facilitates lung epithelial regeneration

Abstract

The mammalian lung is a highly complex organ due to its branched, tree-like structure and diverse cellular composition. Recent efforts using state-of-the-art genetic lineage tracing and single-cell transcriptomics have helped reduce this complexity and delineate the ancestry and fate of various cell subpopulations during organogenesis, homeostasis and repair after injury. However, mesenchymal cell heterogeneity and function in development and disease remain a longstanding issue in the lung field. In this study, we break down smooth muscle heterogeneity into the constituent subpopulations by combining in vivo lineage tracing, single-cell RNA sequencing and in vitro organoid cultures. We identify a repair-supportive mesenchymal cell (RSMC) population that is distinct from pre-existing airway smooth muscle cells (ASMC) and is critical for regenerating the conducting airway epithelium. Progenitors of RSMCs are intertwined with airway smooth muscle, undergo active WNT signaling, transiently acquire the expression of the smooth muscle marker ACTA2 in response to epithelial injury and are marked by PDGFRα expression. Our data simplify the cellular complexity of the peribronchiolar domain of the adult lung and represent a forward step towards unraveling the role of mesenchymal cell subpopulations in instructing epithelial behavior during repair processes.

Crosstalk of Airway Smooth Muscle and Epithelial Cells in Chronic Lung Diseases

“…This action allows ASMCs to form an airway epithelial stem cell niche that services BECs repair (62). In this aspect, Moiseenko et al reported this BECs-repair supporting ASMC population is distinct from pre-existing airway smooth muscle cells and is critical for renewing BECs of the adult lung (63). Nevertheless, in a recently published study, young et al reported that differentiation of airway smooth muscle during lung development is unnecessary for lung branching morphogenesis in mice.…”