Transcriptomic Signature-Guided Depletion of Intermediate Alveolar Epithelial Cells Ameliorates Pulmonary Fibrosis in Mice

Authors

• Fei Peng
• Chun-Sun Jiang
• Zhen Zheng
• Shahram Aliyari
• Dan Shan
• Aaryan Sabharwal
• Qinyan Yin
• Shigeki Saito
• Chao He
• Ivan O Rosas
• Joseph A Lasky
• Victor J Thannickal
• Yong Zhou

Language

English

Publication Date

1-10-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-68354-y

PMID

41519994

PMCID

PMC12905394

PubMedCentral® Posted Date

1-10-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Single-cell RNA sequencing (scRNA-seq) has identified intermediate epithelial states in pulmonary fibrosis, including KRT5-/KRT17+ aberrant basaloid cells in humans and Krt8+ alveolar differentiation intermediates (ADIs) in mice. Their functional contributions to fibrogenesis, however, remain unclear. Here, we introduce an RNA-sensing-dependent protein translation technology that enables selective targeting of Krt8+ ADI cells in vitro and in vivo. Transcriptomic analysis revealed Small Proline-Rich Protein 1 A (SPRR1A) mRNA as a shared marker of murine Krt8+ ADIs and human KRT5-/KRT17+ basaloid cells, distinguishing them from other lung cell populations. Using programmable RNA sensors, we demonstrated selective EGFP-labeling of Krt8+ ADI cells in vivo, which faithfully recapitulated their transcriptomic and phenotypic features. To test function, we developed an RNA-sensing-driven diphtheria toxin receptor (DTR) system for conditional ablation of Sprr1a+ cells. Targeted depletion markedly reduced fibrosis in bleomycin-injured mice, establishing transitional epithelial cells as pathogenic drivers and highlighting their potential as therapeutic targets in pulmonary fibrosis.

Keywords

Animals, Pulmonary Fibrosis, Mice, Humans, Transcriptome, Alveolar Epithelial Cells, Bleomycin, Cornified Envelope Proline-Rich Proteins, Cell Differentiation, Mice, Inbred C57BL, Gene Expression Profiling, Male, Disease Models, Animal, Pulmonary Alveoli, Single-Cell Gene Expression Analysis, Female, Lung

Published Open-Access

yes

Recommended Citation

Peng, Fei; Jiang, Chun-Sun; Zheng, Zhen; et al., "Transcriptomic Signature-Guided Depletion of Intermediate Alveolar Epithelial Cells Ameliorates Pulmonary Fibrosis in Mice" (2026). Faculty, Staff and Students Publications. 6790.
https://digitalcommons.library.tmc.edu/baylor_docs/6790