Lef1 Promotes Foxi1-Dependent Ionocyte Specification by Airway Submucosal Gland Progenitors
- 1University of Alabama at Birmingham
Abstract
Pulmonary ionocytes are rare cells in submucosal gland (SMG)-containing airways thought to have specialized ion transport properties that regulate airway surface fluid and mucus composition. The origins of pulmonary ionocytes remain unclear, but their association with airway SMGs suggests they may arise from specialized progenitors in this compartment. We show that mouse glandular myoepithelial cells (GMECs) have a unique capacity to specify ionocytes enriched in the Cftr channel. The Lef1 transcription factor was both necessary and sufficient to promote GMEC specification of ionocytes in mouse trachea, 3D organoids, and/or air-liquid interface (ALI) cultures. Overexpression of Lef1 (Lef1OE) in GMECs produced ionocyte-enriched epithelia with enhanced Cftr-mediated chloride, bicarbonate, and fluid transport properties. Moreover, Foxi1 knockout in Lef1OE GMECs prevented ionocyte formation while promoting specification of Cftr-expressing secretory cells. These findings provide a progenitor relationship for the anatomical association of ionocytes with SMGs and a transcriptional framework for coordinated specification of CFTR-expressing ionocytes and secretory cells.
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BibTeX
@misc{shahin2026lef1,
title = {{Lef1 Promotes Foxi1-Dependent Ionocyte Specification by Airway Submucosal Gland Progenitors}},
author = {W. Shahin and J. Hajibabazade and O. Snyder and G. Fritz and F. Yuan and V. Ievlev and T. Lynch and C. A. Yeaman and J. F. Engelhardt},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758987},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758987v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Lef1 Promotes Foxi1-Dependent Ionocyte Specification by Airway Submucosal Gland Progenitors
AU - W. Shahin
AU - J. Hajibabazade
AU - O. Snyder
AU - G. Fritz
AU - F. Yuan
AU - V. Ievlev
AU - T. Lynch
AU - C. A. Yeaman
AU - J. F. Engelhardt
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758987
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758987v1
AB - Pulmonary ionocytes are rare cells in submucosal gland (SMG)-containing airways thought to have specialized ion transport properties that regulate airway surface fluid and mucus composition. The origins of pulmonary ionocytes remain unclear, but their association with airway SMGs suggests they may arise from specialized progenitors in this compartment. We show that mouse glandular myoepithelial cells (GMECs) have a unique capacity to specify ionocytes enriched in the Cftr channel. The Lef1 transcription factor was both necessary and sufficient to promote GMEC specification of ionocytes in mouse trachea, 3D organoids, and/or air-liquid interface (ALI) cultures. Overexpression of Lef1 (Lef1OE) in GMECs produced ionocyte-enriched epithelia with enhanced Cftr-mediated chloride, bicarbonate, and fluid transport properties. Moreover, Foxi1 knockout in Lef1OE GMECs prevented ionocyte formation while promoting specification of Cftr-expressing secretory cells. These findings provide a progenitor relationship for the anatomical association of ionocytes with SMGs and a transcriptional framework for coordinated specification of CFTR-expressing ionocytes and secretory cells.
ER -