Stem Cell Biology of Airway Submucosal Glands during Development and Disease

John F. Engelhardt

doi:10.1096/fasebj.2018.32.1_supplement.236.1

Lineage‐tracing studies in the mouse lung suggest that multiple region‐specific progenitors contribute to regenerative plasticity of the airway epithelium. Airway submucosal glands (SMGs) are thought to house stem cell niches for the surface airway epithelium; however, the phenotype of the SMG‐derived progenitor cells remains unclear. SMGs are tubuloacinar structures embedded within the mesenchyme beneath the surface of all cartilaginous airways in humans and the proximal trachea of mice. These structures secrete important factors that regulate airway clearance and maintain sterility at homeostasis and in response to injury and infection. Secretory functions of SMGs are severely affected in cystic fibrosis, a genetic disease caused by mutation in the cystic fibrosis transmembrane conductance regulator, and disease‐associated alterations in neuropeptide (CGRP) expression alter the slowly cycling stem cell niches of SMGs. In this context, CGRP acts as both a secretagogue to stimulate gland secretion following injury—a response defected in cystic fibrosis—and a mitogen of glandular progenitor cells. To better define the contribution of SMG stem cells in airway regeneration and abnormalities to these processes in cystic fibrosis, we have dissected Wnt‐regulated mechanism that control both the formation of glandular stem cell niches during development and lineage‐commitment of glandular stem cells during airway regenerative responses following injury. Using lineage tracing in mice, we demonstrate that multipotent glandular myoepithelial cells form very early during SMG development in a Wnt/TCF‐dependent manner. In the adult mouse trachea, SMG myoepithelial cells can give rise to seven cell types in the proximal airway following severe injury. Similar to the stem cell program adopted during SMG development, Wnt/TCF signals appear to control self‐renewal and lineage commitment of glandular myoepithelial stem cells following injury. These studies clarify important stem cell targets for therapy in the cystic fibrosis lung. Support or Funding Information NIDDK This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.

Stem Cell Biology of Airway Submucosal Glands during Development and Disease

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