ABSTRACT
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin-induced fibrotic lungs of young and aged mice, at 3 time points corresponding to the peak of fibrosis, regeneration and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC which display typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The organization of the manuscript has been extensively modified. New data have been added, including a complete reanalysis of the spatial transcriptomic experiment (Fig.1 and suppl. Fig. S1), the validation of several markers in specific subpopulations using RNA FISH (new panels in Fig. 3, 4 & 5), the addition of statistics for all quantification analyses, the re-analysis of the velocity approach (Fig. 6) as well as functional studies (Suppl. Fig. S4). The author list and affiliations have been updated. Supplemental files have been updated (new supplemental tables). References have been updated.
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE234199
