Tuft cells shape airway remodeling by eliciting OXGR1- and SOX9-dependent stem cell programs

Area of Science:

• Pulmonary Medicine
• Stem Cell Biology
• Immunology

Background:

• Tissue-resident stem cells are crucial for repairing barrier tissues.
• The local signals coordinating repair versus remodeling remain largely unknown.

Purpose of the Study:

• To identify local cues that regulate airway repair and remodeling after injury.
• To elucidate the cellular and molecular mechanisms driving airway remodeling.

Main Methods:

• Murine models of airway injury
• Fate mapping studies
• Genetic null strains
• Analysis of SOX9 expression in airway stem cells

Main Results:

• Tuft epithelial cells signal via cysteinyl leukotrienes (CysLTs) to OXGR1 on submucosal stem cells.
• This activates SOX9+ submucosal gland progenitors, leading to aberrant epithelial repair and airway remodeling.
• Selective deletion of SOX9 in airway stem cells prevented remodeling and restored epithelial integrity.
• The identified tuft cell-OXGR1-SOX9 circuit was also detected in human sinus mucosa.

Conclusions:

• A novel circuit involving tuft cells, OXGR1, and SOX9 drives airway remodeling post-injury.
• Targeting SOX9 in airway stem cells offers a potential strategy to prevent airway remodeling.
• This mechanism is conserved and relevant to human airway tissues.