A mesothelial differentiation gateway drives fibrosis

Area of Science:

• Cell Biology
• Organogenesis
• Genetics

Background:

• Mesothelial cells form a crucial epithelial lining for internal organs.
• The function, evolution, and genetic regulation of mesothelial cells, particularly in disease, remain poorly understood.

Purpose of the Study:

• To create a comprehensive single-cell transcriptomic atlas of mesothelium in healthy and diseased states across species.
• To identify conserved cellular states and genetic drivers in mesothelial cells during disease.
• To investigate the role of metabolic pathways in mesothelial cell differentiation and fibrosis.

Main Methods:

• Single-cell RNA sequencing of mesothelium from mouse and human organs.
• Bioinformatic analysis to identify cell states and genetic regulation.
• In vivo mouse models of lung injury.
• Viral vector-mediated gene manipulation in mice.

Main Results:

• A detailed transcriptomic map of mesothelial cells across diverse organs and conditions was generated.
• Conserved activated states of mesothelial cells in response to disease were identified.
• A common metabolic pathway regulating differentiation into proteolytic, inflammatory, and fibrotic cells was discovered.
• Metabolic reprogramming of mesothelial cells using Ifi27l2a and Crip1 inhibited differentiation and protected mouse lungs from fibrosis.

Conclusions:

• Mesothelial cells are key players and a potential gateway to fibrotic diseases.
• Targeting mesothelial cell metabolism offers a promising therapeutic strategy to combat fibrosis.
• These findings open new translational avenues for treating fibrotic conditions across various clinical indications.