Aging affects reprogramming of pulmonary capillary endothelial cells after lung injury

<bold>Introduction:</bold> Lung regeneration is hampered by aging, which increases susceptibility to pathologies such as fibrosis. While successful alveolar regeneration after injury depends on pulmonary capillary endothelial cells (PCEC) reprogramming, the steps involving PCEC during lung resolution as well as the influence of aging are unknown. <bold>Methods:</bold> We used scRNA-seq and spatial transcriptomics to compare the transcriptome of bleomycin-induced fibrotic lungs of young and aged mice, at 3 time points corresponding to the peak of fibrosis (14 days), regeneration (28 days) and resolution (60 days). <bold>Results:</bold> We found that lung injury shifts the transcriptomic profiles of PCEC cell types, with three prominent signatures. These signatures are characterized by the overexpression of Lrg1 and are associated with pro-angiogenic signaling, potentially supported by adjacent cell types into the alveolar niche. These signatures were not equally maintained through the resolution process and between young and old animals. Moreover, part of this set of resolution-associated markers was also detected in pulmonary endothelial cells from samples of patients with idiopathic pulmonary fibrosis. Finally, we found that aging also altered the transcriptome of general capillary cells which display typical pro-fibrotic and pro-inflammatory features. <bold>Conclusions:</bold> We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation contributing to the persistent fibrotic process typical of human pathology.