Aging affects reprogramming of pulmonary capillary endothelial cells after lung injury in male mice

Marin Truchi ^1,2, Marine Gautier-Isola ^1,2, Grégoire Savary ³

¹Université Côte d'Azur, UMR CNRS 7275 Inserm U1323, IPMC, Valbonne, France.
²IHU RespirERA, Université Côte d'Azur, Nice, France.
³Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 CNRS - U1277 Inserm - CANTHER, Lille, France.
⁴Cardio-Pulmonary Institute (CPI) and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Justus-Liebig-University (JLU), Giessen, Germany.
⁵Institute for Lung Health (ILH), Giessen, Germany.
⁶Laboratory of Clinical and Experimental Pathology and Biobank Côte d'Azur BB-0033-00025, Centre Hospitalier Universitaire de Nice, Nice, France.
⁷Université Côte d'Azur, UMR 7413 CNRS Inserm U1081, IRCAN, Nice, France.
⁸Department of Pulmonary Medicine and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Nice, France.
⁹European IPF Registry and Biobank, Giessen, Germany.
¹⁰Lung Clinic, Agaplesion Evangelisches Krankenhaus Mittelhessen, Giessen, Germany.
¹¹BioSanté unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France.
¹²3IA Côte d'Azur, Université Côte d'Azur, Sophia Antipolis, France.
¹³Université Côte d'Azur, UMR CNRS 7275 Inserm U1323, IPMC, Valbonne, France. mari@unice.fr.
¹⁴IHU RespirERA, Université Côte d'Azur, Nice, France. mari@unice.fr.

⁰Université Côte d'Azur, UMR CNRS 7275 Inserm U1323, IPMC, Valbonne, France.

Nature Communications +

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August 6, 2025

View abstract on PubMed

Summary

Aging impairs lung regeneration, altering pulmonary capillary endothelial cells (PCEC) and their response to injury. These age-related changes in PCEC may drive persistent fibrosis in aging lungs.

Area Of Science

Pulmonary Medicine
Cell Biology
Aging Research

Background

Aging is a major risk factor for fibrotic diseases, characterized by impaired tissue regeneration.
Fibrotic diseases, such as idiopathic pulmonary fibrosis, significantly impact lung function and patient outcomes.

Purpose Of The Study

To investigate the impact of aging on lung regeneration following bleomycin-induced injury.
To compare the transcriptomic profiles of pulmonary capillary endothelial cells (PCEC) in young versus aged mice during fibrosis resolution.
To identify age-associated molecular alterations in PCEC that may contribute to persistent lung fibrosis.

Main Methods

Longitudinal single-cell RNA sequencing and spatial transcriptomics were employed.
Transcriptomic analysis was performed on bleomycin-induced fibrotic lungs from young and aged male mice at three distinct time points (peak fibrosis, regeneration, resolution).
PCEC subpopulations were analyzed for differential gene expression and signaling pathway alterations.

Main Results

Lung injury induced transcriptomic shifts in three PCEC subpopulations, associated with pro-angiogenic signaling and Lrg1 expression.
The resolution of fibrosis differed significantly between young and aged mice, with altered PCEC marker expression in aged individuals.
Resolution-associated markers found in aged PCEC were also detected in PCEC from patients with idiopathic pulmonary fibrosis.
Aging altered PCEC transcriptomes, exhibiting pro-fibrotic and pro-inflammatory characteristics.

Conclusions

Age-associated alterations in specific PCEC subpopulations may hinder lung progenitor cell differentiation.
These PCEC changes likely contribute to the persistent fibrotic processes observed in aging lungs and human fibrotic lung diseases.
Targeting age-related PCEC dysfunction presents a potential therapeutic strategy for fibrotic lung diseases.