Shawyon P. Shirazi, Nicholas M. Negretti, Christopher S. Jetter, Alexandria L. Sharkey, Shriya Garg, Meghan E. Kapp, Devan Wilkins, Gabrielle Fortier, Saahithi Mallapragada, Nicholas E. Banovich, Laurie C. Eldredge, Gail H. Deutsch, Christopher V. E. Wright, David B. Frank, Jonathan A. Kropski, Jennifer M. S. Sucre
Vanderbilt University Medical Center and Vanderbilt University. Translational Genomics Research Institute. Seattle Children’s Hospital. Children’s Hospital of Philadelphia. Department of Veterans Affairs Medical Center.
United States
Nature Communications
Nat Commun 2025; 16:
DOI: 10.1038/s41467-025-60371-7
Abstract
Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To identify potential cellular and molecular drivers of BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs with evolving BPD and BPD + PH compared to term infants. Examination of endothelial cells reveals a unique, aberrant capillary cell-state in BPD + PH defined by ANKRD1 expression. Within the alveolar parenchyma in infants with BPD/BPD + PH, predictive signaling analysis identifies surprising deficits in the semaphorin guidance-cue pathway, with decreased expression of pro-angiogenic transcription factor FOXF1. Loss of semaphorin signaling is replicated in a murine BPD model and in humans with causal FOXF1 mutations for alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between developmental programs underlying BPD and ACDMPV and uncovering a critical role for semaphorin signaling in normal lung development.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Class III. Pulmonary Hypertension Associated with Developmental Diseases of the Lung
Pulmonary Vascular Pathology
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes