p53 maintains lineage fidelity during lung capillary injury-repair in neonatal hyperoxia

Lisandra Vila Ellis; Jonathan D. Bywaters; Amanda Ceas; Yun Liu; Jennifer M.S. Sucre; Jichao Chen

doi:10.1172/jci.insight.182880

p53 maintains lineage fidelity during lung capillary injury-repair in neonatal hyperoxia

Lisandra Vila Ellis,¹ Jonathan D. Bywaters,¹ Amanda Ceas,¹ Yun Liu,¹ Jennifer M.S. Sucre,² and Jichao Chen³

Published August 5, 2025 - More info

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Abstract

Bronchopulmonary dysplasia (BPD), a prevalent and chronic lung disease affecting premature newborns, results in vascular rarefaction and alveolar simplification. Although the vasculature has been recognized as a main player in this disease, the recently found capillary heterogeneity and cellular dynamics of endothelial subpopulations in BPD remain unclear. Here, we show Cap2 cells are damaged during neonatal hyperoxic injury, leading to their replacement by Cap1 cells which, in turn, significantly decline. Single cell RNA-seq identifies the activation of numerous p53 target genes in endothelial cells (ECs), including Cdkn1a (p21). While global deletion of p53 results in worsened vasculature, endothelial-specific deletion of p53 reverses the vascular phenotype and improves alveolar simplification during hyperoxia. This recovery is associated with the emergence of a transitional EC state, enriched for oxidative stress response genes and growth factors. Notably, this transitional EC gene signature is conserved in an aberrant capillary population identified in human BPD with pulmonary hypertension, underscoring the biological and clinical relevance of our findings. These results reveal a key role for p53 in maintaining endothelial lineage fidelity during pulmonary capillary repair following hyperoxic injury and highlight the critical contribution of the endothelium to BPD pathogenesis.

p53 maintains lineage fidelity during lung capillary injury-repair in neonatal hyperoxia

Lisandra Vila Ellis,¹ Jonathan D. Bywaters,¹ Amanda Ceas,¹ Yun Liu,¹ Jennifer M.S. Sucre,² and Jichao Chen³

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p53 maintains lineage fidelity during lung capillary injury-repair in neonatal hyperoxia

Lisandra Vila Ellis,1 Jonathan D. Bywaters,1 Amanda Ceas,1 Yun Liu,1 Jennifer M.S. Sucre,2 and Jichao Chen3

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Lisandra Vila Ellis,¹ Jonathan D. Bywaters,¹ Amanda Ceas,¹ Yun Liu,¹ Jennifer M.S. Sucre,² and Jichao Chen³