Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth

Zanini, Fabio; Che, Xibing; Knutsen, Carsten; Liu, Min; Suresh, N.; Domingo-Gonzalez, Racquel; Dou, Steve H.; Zhang, Daoqin; Pryhuber, Gloria S.; Jones, Robert C.; Quake, Stephen R.; Cornfield, David N.; Alvira, Cristina M.

doi:10.1016/j.isci.2023.106097

Cited by 10 publications

(8 citation statements)

References 125 publications

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“…4F and Supplemental table 4). Conversely, we found in young gCap an enrichment of transcription factors associated with vascular homeostasis and repair such as Klf2, Klf10 and Peg3 [44][45][46][47]. In PBS-treated mice, comparison between old and young gCap revealed even more gene modulations, which were associated to multiple functions (Fig.…”

Section: Aged Mouse Lung Gcap Cells Exhibit Pro-inflammatory and Pre-...mentioning

confidence: 78%

Lung injury shifts pulmonary capillary endothelial cells towards regeneration-associated Lrg1+ subpopulations with delayed dynamics in aged mice

Truchi,

Savary,

Cadis

et al. 2023

Preprint

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Introduction and main objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible interstitial lung disease (ILD), that increases dramatically in incidence and prevalence with age. While successful alveolar regeneration after injury depends on pulmonary capillary endothelial cells (PCEC) reprogramming, the steps involving PCEC during lung injury and resolution as well as the influence of aging are unknown. Methods: We used single-cell RNA-seq (scRNA-seq) and spatial transcriptomics to compare the transcriptome of bleomycin-induced fibrotic lungs of young (7 weeks) and aged (18 months) mice, at 3 time points corresponding to the peak of fibrosis (14 days), regeneration (28 days) and resolution (60 days). Results: Among the 44541 sequenced and annotated cells, we confirmed the transcriptomic dynamics of several cell types including macrophages, in which conversion is conserved between young and aged mice. We also found that lung injury shifts the transcriptomic profiles of recently described PCEC cell types, with 4 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 (ECs) from IPF samples. Finally, we found that aging also altered the transcriptome of general capillary cells (gCap) which display typical pro-fibrotic and pro-inflammatory features. Conclusions: We provide a detailed characterization of the cellular dynamics associated with fibrosis development and resolution in young and aged lungs and 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.

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Section: Aged Mouse Lung Gcap Cells Exhibit Pro-inflammatory and Pre-...mentioning

confidence: 78%

Lung injury shifts pulmonary capillary endothelial cells towards regeneration-associated Lrg1+ subpopulations with delayed dynamics in aged mice

Truchi,

Savary,

Cadis

et al. 2023

Preprint

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“…1 D and E). Annotation of these cell sub-populations was done based on prior publications focused on the developing and adult murine lungs [ 23 , [33] , [34] , [35] , [36] , [37] ]. Cellular annotation markers and their distribution among different cellular sub-clusters were also labeled ( Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of recovery from neonatal hyperoxic lung injury by sex as a biological variable

Cantu,

Gutierrez,

Dong

et al. 2023

Redox Biology

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“…Though prior transcriptomic studies of the neonatal lung have employed hyperoxia as a lung injury model 18 , this report is the first to identify Acta1 + cells in the lung. The study design likely accounts for the discovery of the Acta1 + cells as the cell digestion protocol was carefully optimized 11 , 66 . Moreover, the read depth per cell was significantly greater than reported in prior studies (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity

Zanini,

Che,

Suresh

et al. 2024

Sci Rep

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Rapid expansion of the pulmonary microvasculature through angiogenesis drives alveolarization, the final stage of lung development that occurs postnatally and dramatically increases lung gas-exchange surface area. Disruption of pulmonary angiogenesis induces long-term structural and physiologic lung abnormalities, including bronchopulmonary dysplasia, a disease characterized by compromised alveolarization. Although endothelial cells are primary determinants of pulmonary angiogenesis, mesenchymal cells (MC) play a critical and dual role in angiogenesis and alveolarization. Therefore, we performed single cell transcriptomics and in-situ imaging of the developing lung to profile mesenchymal cells during alveolarization and in the context of lung injury. Specific mesenchymal cell subtypes were present at birth with increasing diversity during alveolarization even while expressing a distinct transcriptomic profile from more mature correlates. Hyperoxia arrested the transcriptomic progression of the MC, revealed differential cell subtype vulnerability with pericytes and myofibroblasts most affected, altered cell to cell communication, and led to the emergence of Acta1 expressing cells. These insights hold the promise of targeted treatment for neonatal lung disease, which remains a major cause of infant morbidity and mortality across the world.

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Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth

Cited by 10 publications

References 125 publications

Lung injury shifts pulmonary capillary endothelial cells towards regeneration-associated Lrg1+ subpopulations with delayed dynamics in aged mice

Lung injury shifts pulmonary capillary endothelial cells towards regeneration-associated Lrg1+ subpopulations with delayed dynamics in aged mice

Modulation of recovery from neonatal hyperoxic lung injury by sex as a biological variable

Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity

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