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Transcriptomic signature-guided depletion of intermediate alveolar epithelial cells ameliorates pulmonary fibrosis in mice

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 unclea...

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Main Authors: Peng, Fei (Author) , Jiang, Chun-sun (Author) , Zheng, Zhen (Author) , Aliyari, Shahram (Author) , Shan, Dan (Author) , Sabharwal, Aaryan (Author) , Yin, Qinyan (Author) , Saito, Shigeki (Author) , He, Chao (Author) , Rosas, Ivan O. (Author) , Lasky, Joseph (Author) , Thannickal, Victor J. (Author) , Zhou, Yong (Author)
Format: Article (Journal)
Language:English
Published: 10 january 2026
In: Nature Communications
Year: 2026, Volume: 17, Pages: 1-13
ISSN:2041-1723
DOI:10.1038/s41467-026-68354-y
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-026-68354-y
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-026-68354-y
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 19.06.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-026-68354-y

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