Single-cell RNA-seq characterization of lung fibrosis resolution reveals a delayed capillary endothelial signature associated with alveolar regeneration in aged mice - 17/02/23

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible interstitial lung disease, which incidence and prevalence greatly increase with age. While successful alveolar regeneration after injury depends on capillary endothelial cells (EC) reprogramming, the steps involving capillary ECs during lung injury and resolution as well as the influence of aging are unknown.

We used single-cell RNA-seq and spatial transcriptomics to compare the transcriptome of bleomycin-induced fibrotic lungs of young (7 weeks) and old (18 months) mice, at 3 time points corresponding to the peak of fibrosis (14 days), regeneration (28 days) and resolution (60 days) (Fig. 1).

Among the 44,541 sequenced and annotated cells, we confirmed the transcriptomic dynamics of several cell types including macrophages [1Aran D., Looney A.P., Liu L., Wu E., Fong V., Hsu A., et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage Nat Immunol 2019 ;  20 : 163-172 [cross-ref]

Cliquez ici pour aller à la section Références], which conversion is conserved between young and aged mice. We also found that lung injury shifts the transcriptomic profiles of recently described capillary EC subpopulations [2Gillich A., Zhang F., Farmer C.G., Travaglini K.J., Tan S.Y., Gu M., et al. Capillary cell-type specialization in the alveolus Nature 2020 ;  586 : 785-789 [cross-ref]

Cliquez ici pour aller à la section Références], with 4 recognizable signatures. These signatures were not equally maintained through the resolution process and between young and old animals. Several of these specific capillary EC markers were also identified in IPF fibrotic lesions. Inferences of cellular communications suggest that a pro-angiogenic signature is supported by adjacent cell types into the alveolar niche.

We provide a detailed characterization of capillary EC subsets emerging after lung injury and contributing to alveolar regeneration.