Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression

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 () and Jennifer M. S. Sucre ()
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Shawyon P. Shirazi: Vanderbilt University Medical Center
Nicholas M. Negretti: Vanderbilt University Medical Center
Christopher S. Jetter: Vanderbilt University Medical Center
Alexandria L. Sharkey: Vanderbilt University Medical Center
Shriya Garg: Vanderbilt University Medical Center
Meghan E. Kapp: Case Western Reserve University Hospitals
Devan Wilkins: Vanderbilt University Medical Center
Gabrielle Fortier: Vanderbilt University
Saahithi Mallapragada: Translational Genomics Research Institute
Nicholas E. Banovich: Translational Genomics Research Institute
Laurie C. Eldredge: Seattle Children’s Hospital
Gail H. Deutsch: Seattle Children’s Hospital
Christopher V. E. Wright: Vanderbilt University
David B. Frank: Penn-CHOP Lung Biology Institute
Jonathan A. Kropski: Vanderbilt University
Jennifer M. S. Sucre: Vanderbilt University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60371-7

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