Single-cell division tracing and transcriptomics reveal cell types and differentiation paths in the regenerating lung

Area of Science:

• Pulmonary Medicine
• Regenerative Biology
• Single-cell Genomics

Background:

• Lung epithelial regeneration is crucial for treating lung diseases.
• Identifying specific cell roles in regeneration is vital for therapeutic development.

Purpose of the Study:

• To characterize the molecular and cellular processes of distal lung epithelial regeneration.
• To create a single-cell atlas of lung regeneration responses to injury.

Main Methods:

• Utilized mouse models with diphtheria toxin-induced epithelial damage.
• Employed GFP-labeling for tracking dividing cells.
• Performed single-cell transcriptomics to analyze cellular responses.

Main Results:

• Identified Krt13+ basal and Krt15+ club cells in regeneration.
• Discovered an intermediate cell state between basal and goblet cells.
• Revealed goblet cells as actively dividing progenitors and adventitial fibroblasts as supporting cells.
• Found persistent diphtheria toxin-expressing cells with inflammatory profiles resembling a COVID-19 patient lung population.

Conclusions:

• Provided a comprehensive single-cell atlas of distal lung regeneration.
• Characterized early cellular and transcriptional responses to lung injury, including proliferation and differentiation.
• Highlighted potential therapeutic targets and insights into lung disease pathogenesis.