Journal
DEVELOPMENTAL CELL
Volume 56, Issue 11, Pages 1646-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2021.04.027
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Funding
- Molecular Atlas of Lung Development Program, Human Tissue Core [U01HL122700/U01HL148861]
- NIH [S10RR027050]
- Genetically Modified Mouse Model Shared Resource of the NIH/NCI Cancer Center Support grant at Columbia University [P30CA013696, R01HL132991]
- Young Investigator Research Program [588020-D01907]
- [R01HL152293]
- [R01HL132996]
- [R01DK113144]
- [R01DK100342]
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The study reveals an unexpected role of VEGFa/KDR signaling in defending against mucous metaplasia, potentially offering a therapeutic target for common airway pathologies.
Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.
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