Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia.

Creator(s)

Sheng Xia, Children's Mercy HospitalFollow
Lisandra Vila Ellis
Konner Winkley, Children's Mercy Kansas City
Heather Menden, Children's Mercy HospitalFollow
Sherry M. Mabry, Children's Mercy HospitalFollow
Aparna Venkatraman, Children's Mercy HospitalFollow
Daniel A. Louiselle, Children's Mercy HospitalFollow
Margaret Gibson, Children's Mercy HospitalFollow
Elin Grundberg, Children's Mercy HospitalFollow
Jichao Chen
Venkatesh Sampath, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

2-1-2023

Identifier

DOI: 10.1152/ajplung.00252.2022

Abstract

Hyperoxia disrupts lung development in mice and causes bronchopulmonary dysplasia (BPD) in neonates. To investigate sex-dependent molecular and cellular programming involved in hyperoxia, we surveyed the mouse lung using single cell RNA sequencing (scRNA-seq), and validated our findings in human neonatal lung cells in vitro. Hyperoxia-induced inflammation in alveolar type (AT) 2 cells gave rise to damage-associated transient progenitors (DATPs). It also induced a new subpopulation of AT1 cells with reduced expression of growth factors normally secreted by AT1 cells, but increased mitochondrial gene expression. Female alveolar epithelial cells had less EMT and pulmonary fibrosis signaling in hyperoxia. In the endothelium, expansion of Car4+ EC (Cap2) was seen in hyperoxia along with an emergent subpopulation of Cap2 with repressed VEGF signaling. This regenerative response was increased in females exposed to hyperoxia. Mesenchymal cells had inflammatory signatures in hyperoxia, with a new distal interstitial fibroblast subcluster characterized by repressed lipid biosynthesis and a transcriptomic signature resembling myofibroblasts. Hyperoxia-induced gene expression signatures in human neonatal fibroblasts and alveolar epithelial cells in vitro resembled mouse scRNA-seq data. These findings suggest that neonatal exposure to hyperoxia programs distinct sex-specific stem cell progenitor and cellular reparative responses that underpin lung remodeling in BPD.

Journal Title

American journal of physiology. Lung cellular and molecular physiology

Volume

324

Issue

2

First Page

123

Last Page

140

MeSH Keywords

Infant, Newborn; Male; Female; Animals; Mice; Humans; Bronchopulmonary Dysplasia; Transcriptome; Hyperoxia; Animals, Newborn; Lung; Disease Models, Animal

Keywords

bronchopulmonary dysplasia; hyperoxia; neonates; pulmonary; single-cell RNA sequencing

Comments

Grant support

• R01 HL130129/HL/NHLBI NIH HHS/United States
• R01 HL153511/HL/NHLBI NIH HHS/United States
• 1R01HL128374-05/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• 5K99HL155845/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• R01HL153511/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)

• R01HL130129/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)

Recommended Citation

Xia S, Vila Ellis L, Winkley K, et al. Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2023;324(2):L123-L140. doi:10.1152/ajplung.00252.2022