545 - Inhaled Surfactant and Preterm Umbilical Cord Derived Mesenchymal Stem Cell Exosomes for Prevention of Murine Bronchopulmonary Dysplasia

Publication Number: 3526.545

Bryston Chang, University of California, Irvine, School of Medicine, Orange, CA, United States; Fayez Bany-Mohammed, University of California, Irvine, Irvine, CA, United States; Cherry Uy, University of California, Irvine, School of Medicine, Orange, CA, United States; Muhammad Aslam, UC Irvine, Orange, CA, United States

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting preterm infants, characterized by impaired alveolarization and pulmonary hypertension. Studies have demonstrated that intravenous administration of mesenchymal stem cells (MSCs) or their exosomes (MSC-exo) can prevent BPD in murine models. Direct pulmonary delivery of MSC-exo along with exogenous surfactant offers several potential advantages, including higher local concentration, reduced systemic exposure, and enhanced therapeutic efficiency. To leverage these benefits, we developed a novel inhalation system for direct delivery of MSC-exo to the lungs.

Objective: We hypothesized that inhalation of surfactant combined with preterm MSC-exo is both feasible and therapeutically beneficial in preventing hyperoxia-induced BPD. The primary objective was to evaluate lung injury, pulmonary function, and pulmonary hypertension in hyperoxia-exposed murine models treated with surfactant plus MSC-exo inhalation.

Design/Methods: MSCs were derived from preterm umbilical cords (24-28 weeks' gestational age), and exosomes were isolated and characterized. FVB mice were exposed to hyperoxia (90% O₂) within 24 hours of birth, while control mice remained in normoxia (21% O₂). One treatment group received inhalation of MSC-exo (0.1 μg/g body weight) combined with surfactant (1 mg/kg) at 24 and 48 hours of life. Comparison groups received MSC-exo alone or human skin epithelium cell-derived exosomes (SEC-exo). Mice were maintained in their respective oxygen conditions until day 14, followed by normoxia until day 28. Development of BPD was assessed by pulmonary function testing and echocardiography.

Results: Inhalation of surfactant with preterm MSC-exo partially protected against hyperoxia-induced lung injury, showing significant improvements in inspiratory capacity and lung compliance compared with MSC-exo alone or SEC-exo (Fig. 1). This treatment also attenuated pulmonary hypertension, evidenced by reduced right ventricular hypertrophy and improved pulmonary artery acceleration time (Fig. 2). All observed effects were statistically significant, demonstrating that the combination therapy offers enhanced protective effects compared with MSC-exo or control exosomes alone.

Conclusion(s): Direct pulmonary delivery of surfactant combined with MSC-exo is feasible and effectively mitigates hyperoxia-induced BPD in murine models. Ongoing studies are examining the effects of extended treatment duration, dosing optimization, and detailed mechanistic pathways to further enhance efficacy and clinical translatability.

Lung function test via Inspiratory Capacity (IC) and Stat. Compliance (Cst) measurement in Normoxia and Hyperoxia.
Inhalation of Surfactant with Preterm MSC-exo partially protected lung function in hyperoxia compared with controls. Data are presented as mean +/- SD of n=8 mice per group. all results significant using One-way ANOVA with p<0.05

Pulmonary hypertension assessment with Echocardiograms in 28 days old mice in Normoxia and Hyperoxia
Inhalation of Surfactant with preterm MSC-exo partially protected pulmonary hypertension with less RVWT and better PAAT when compared with controls. Data are presented as mean +/- SD of n=8 mice per group. All results significant using one-way ANOVA with p<0.05.