Truchi Marin, Gautier-Isola Marine, Savary Grégoire, Scribe Célia, Lingampally Arun, Cadis Hugo, Baeri Alberto, Magnone Virginie, Girard-Riboulleau Cédric, Arguel Marie-Jeanne, de Schutter Clémentine, Fassy Julien, Boukrout Nihad, Larrue Romain, Martin Nathalie, Rezzonico Roger, Pluquet Olivier, Perrais Michael, Hofman Véronique, Marquette Charles-Hugo, Hofman Paul, Günther Andreas, Ricard Nicolas, Barbry Pascal, Leroy Sylvie, Lebrigand Kevin, Bellusci Saverio, Cauffiez Christelle, Vassaux Georges, Pottier Nicolas, Mari Bernard
Université Côte d'Azur, UMR CNRS 7275 Inserm U1323, IPMC, Valbonne, France.
IHU RespirERA, Université Côte d'Azur, Nice, France.
Nat Commun. 2025 Aug 6;16(1):7234. doi: 10.1038/s41467-025-62431-4.
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 (BLM) -induced fibrotic lungs of young and aged male 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 displays 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.
衰老会通过阻碍损伤后的组织再生增加患纤维化疾病的风险。利用纵向单细胞RNA测序和空间转录组学技术，我们在此比较了博来霉素（BLM）诱导的年轻和老年雄性小鼠纤维化肺在对应纤维化、再生和消退高峰的3个时间点的转录组。我们发现肺损伤改变了三个肺毛细血管内皮细胞（PCEC）亚群的转录组谱。相关特征与具有强Lrg1表达的促血管生成信号相关，并且在年轻和老年动物的消退过程中进展不同。此外，在特发性肺纤维化患者样本的PCEC中也检测到了这组与消退相关标志物的一部分。最后，我们发现衰老也会改变PCEC的转录组，其表现出典型的促纤维化和促炎特征。我们提出，特定PCEC亚群中与年龄相关的改变可能会干扰肺祖细胞的分化过程，从而导致人类病理学中典型的持续性纤维化过程。
