Regionally distinct progenitor cells in the lower airway give rise to neuroendocrine and multiciliated cells in the developing human lung

Abstract

Using scRNA-seq and microscopy, we describe a cell that is enriched in the lower airways of the developing human lung and identified by the unique coexpression of <i>SCGB3A2/SFTPB/CFTR</i>. To functionally interrogate these cells, we apply a single-cell barcode-based lineage tracing method, called CellTagging, to track the fate of <i>SCGB3A2/SFTPB/CFTR</i> cells during airway organoid differentiation in vitro. Lineage tracing reveals that these cells have a distinct differentiation potential from basal cells, giving rise predominantly to pulmonary neuroendocrine cells and a subset of multiciliated cells distinguished by high <i>C6</i> and low <i>MUC16</i> expression. Lineage tracing results are supported by studies using organoids and isolated cells from the lower noncartilaginous airway. We conclude that <i>SCGB3A2/SFTPB/CFTR</i> cells are enriched in the lower airways of the developing human lung and contribute to the epithelial diversity and heterogeneity in this region.