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Multipotent Myoepithelial Progenitor Cells Are Born Early During Airway Submucosal Gland Development

Airway submucosal glands (SMGs) are facultative stem cell niches for the surface epithelium, but the phenotype of the SMG‐derived progenitor cells remains unclear. In other organs, glandular myoepithelial cells (MECs) have been proposed to be multipotent progenitors for luminal cells. We sought to determine the developmental phase during which mouse tracheal glandular MECs are born and whether these primordial MECs are progenitors for other cell phenotypes during SMG morphogenesis. To approach this question, we localized two MEC protein markers (α‐smooth muscle actin [αSMA/ACTA2] and smooth muscle myosin heavy chain 11 [SMMHC]) during various stages of SMG development (placode, elongation, branching, and differentiation) and used ACTA2‐CreERT2 transgenic mice to fate map MEC‐derived lineages during SMG morphogenesis. Protein localization ontogeny studies demonstrated that both αSMA‐ and SMMHC‐expressing cells emerged early following placode formation and during the elongation phase of SMG development. Tamoxifeninduction of newborn ACTA2‐CreERT2 mice led to lineage‐tracing of ~50% of αSMA+ MECs at the tips of invading tubules during the elongation phase and these cells contributed to ~25% of αSMA+ MECs in the fully formed gland by 21 days. During the differentiation phase of gland development, ~33% MEC derived cells that were lineage‐marked at birth gave rise to αSMA‐negative glandular cell types by 21 days, including serous, mucous, and duct cells. By contrast, lineage‐traced MECs did not contribute to cell types in the surface airway epithelium. These findings demonstrate that primordial MECs born early during SMG morphogenesis are multipotent progenitors with the capacity to differentiate into other glandular cell types.