Perinatal origins of bronchopulmonary dysplasia—deciphering normal and impaired lung development cell by cell

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TL;DR

Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease of prematurity driven by antenatal insults (e.g., intrauterine growth restriction, chorioamnionitis, preeclampsia) and postnatal injuries (mechanical ventilation, hyperoxia, inflammation) that collectively arrest alveolar and microvascular development. The disease presents with heterogeneous clinical phenotypes and endotypes, and recent single-cell RNA sequencing studies have begun to identify specific cell populations—such as depleted gCap endothelial cells and altered myofibroblast subsets—that underlie the arrested lung development. Understanding these cellular mechanisms is critical for developing targeted therapies, including stem cell and extracellular vesicle-based treatments, to prevent or reverse the lifelong respiratory consequences of BPD.

Full summary

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**Background** Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in children and a leading cause of neonatal morbidity and mortality. Since 1999, BPD has been defined by the need for supplemental oxygen at 36 weeks post-menstrual age and classified into mild, moderate, or severe grades. While advances in neonatal care have improved survival of premature infants, the incidence of BPD has not decreased, particularly among extremely premature infants of lower gestational age. BPD is a multifactorial disease resulting from prematurity, respiratory distress, and subsequent treatments including mechanical ventilation (MV) and oxygen supplementation. Additional risk factors include low birth weight, infection, maternal nutrition, preeclampsia, intrauterine growth restriction (IUGR), prenatal smoke exposure, and potential hereditary components. The "new" BPD phenotype is characterized less by fibrosis and more by a global arrest in alveolar and microvascular development, leading to long-term sequelae including neurodevelopmental changes, impaired lung function, pulmonary vascular disease, cardiac dysfunction, increased susceptibility to viral infections, asthma, and early-onset emphysema.

**Methods** This is a narrative review synthesizing current knowledge on the perinatal origins of BPD. The authors discuss underlying causes and mechanisms, drawing on experimental animal models (rodents, sheep, baboons) and clinical studies. They review evidence from IUGR models (uterine artery ligation, low protein diet, heat exposure), preeclampsia models (genetic BPH/5 mouse, chronic hypoxia, pharmacologic nitric oxide inhibition, surgical reduced uterine perfusion pressure, intraamniotic sFLT-1 injections), and chorioamnionitis models (bacterial lipopolysaccharide administration). The review also covers single-cell RNA sequencing (scRNA-seq) studies of developing lung, including over 300 published datasets, with particular focus on the largest study of hyperoxia-exposed developing mice profiling over 66,000 lung cells at postnatal days 3, 7, and 14. Additionally, the authors review studies on lung stem/progenitor cells including epithelial (basal cells, bronchial alveolar stem cells, AT2 cells), endothelial (endothelial colony-forming cells, c-Kit+ endothelial cells), and mesenchymal stromal cells (MSCs) from bone marrow, umbilical cord, and resident lung populations.

**Key Results** The review identifies several critical findings: (1) IUGR in animal models impairs alveolar and vascular formation, with decreased IGF-1 levels reported in serum of BPD patients and IGF-1 shown to have anti-inflammatory properties and prevent right ventricular hypertrophy in a rat BPD model. (2) Placental dysfunction and preeclampsia are independent risk factors for BPD; a meta-analysis of 211 studies showed placental vascular dysfunction with IUGR or small-for-gestational-age increases BPD and pulmonary hypertension risk. (3) Intraamniotic sFLT-1 injections in rats recapitulate lung growth retardation, abnormal lung function, and right ventricular hypertrophy, with anti-sFLT-1 antibody treatment improving outcomes. (4) Patent ductus arteriosus (PDA) occurs in up to 70% of infants born before 28 weeks gestation, but multiple randomized controlled trials have failed to find a direct causal relationship between PDA and BPD development. (5) Up to 25% of patients with moderate to severe BPD develop pulmonary hypertension. (6) Microbiome studies show decreased bacterial diversity, higher Ureoplasma levels, and lower Staphylococcus levels in tracheal aspirates of preterm infants developing severe BPD. (7) Hyperoxia exposure in mice causes gradual changes in cell composition, with substantial depletion of gCap (general capillary) endothelial cells and increase in Car4+ aCap cells (aerocytes) showing pro-inflammatory and anti-angiogenic gene expression. (8) scRNA-seq revealed transcriptomic shifts in myofibroblasts, pericytes, and Col13a1+ fibroblasts as among the most active signal senders and receivers in the hyperoxic lung. (9) Decreased PDGFRA expression is found in animal hyperoxia BPD models and associated with increased BPD incidence in male patients. (10) Human UC-MSC-derived extracellular vesicles improved alveolar and vascular development, lung function, and right ventricular hypertrophy in hyperoxia-exposed developing mice.

**Clinical Implications** BPD remains a major challenge in neonatal care with lifelong consequences. The recognition of distinct BPD phenotypes (parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed) and endotypes (infection/inflammation vs. placental dysfunction) supports a personalized medicine approach to therapy. The "vascular hypothesis" of BPD pathogenesis suggests potential preventive use of proangiogenic agents. Less invasive ventilation strategies (nasal continuous positive airways pressure, less invasive surfactant administration, minimally invasive surfactant therapy) represent promising approaches to decrease BPD occurrence. Cell-based therapies, particularly MSCs and MSC-derived extracellular vesicles, have shown therapeutic properties in experimental BPD and are in early phase clinical trials. However, the scarcity of human lung tissue from BPD patients limits translation of findings from animal models. Future multi-omics and interdisciplinary approaches, including single-cell technologies, lineage tracing, and spatial transcriptomics, will be essential for identifying rare cell types, cellular dynamics, and novel biomarkers to enable development of personalized preventive and therapeutic strategies.