VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.
Dev Cell
; 56(11): 1646-1660.e5, 2021 06 07.
Article
in En
| MEDLINE
| ID: mdl-34010630
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Vascular Endothelial Growth Factor Receptor-2
/
Vascular Endothelial Growth Factor A
/
Airway Obstruction
/
SOX9 Transcription Factor
/
Metaplasia
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Dev Cell
Year:
2021
Document type:
Article