A correctable immune niche for epithelial stem cell reprogramming and post-viral lung diseases

Area of Science:

• Immunology
• Stem Cell Biology
• Epithelial Biology

Background:

• Epithelial barriers are crucial for defense and repair but susceptible to detrimental remodeling and disease.
• Epithelial stem cells (ESCs) regenerate tissues but can undergo maladaptive reprogramming.
• Understanding the triggers for detrimental ESC reprogramming is vital for disease intervention.

Purpose of the Study:

• To identify the cellular and molecular mechanisms governing basal ESC reprogramming following epithelial injury.
• To investigate the role of monocyte-derived dendritic cells (moDCs) in this process.
• To explore therapeutic strategies targeting this pathway for disease correction.

Main Methods:

• Utilized mouse models of epithelial injury post-respiratory viral infection.
• Investigated Wfdc21-dependent moDC populations and their interaction with basal ESCs.
• Analyzed the GPNMB-CD44 signaling axis.
• Employed antibody blockade of GPNMB or CD44.
• Validated findings in mouse and human basal ESC organoids.

Main Results:

• Identified a Wfdc21-dependent moDC population acting as an early sentinel niche for basal ESC reprogramming.
• Demonstrated that moDC-derived GPNMB signaling to basal ESC receptor CD44 drives reprogramming.
• Showed that timely antibody blockade of GPNMB or CD44 effectively corrected reprogramming and disease phenotypes.
• Confirmed the conserved nature of this control mechanism in human ESC organoids.

Conclusions:

• A novel moDC-mediated signaling pathway (GPNMB-CD44) regulates ESC reprogramming after epithelial injury.
• This pathway represents a critical control point for detrimental tissue remodeling.
• Targeting this pathway offers a promising therapeutic strategy for correcting disease phenotypes associated with epithelial injury.