Human Umbilical Cord Mesenchymal Stem Cell‐Derived Microvesicles Alleviate Bronchopulmonary Dysplasia in Preterm Rats by Inhibiting Neutrophil Extracellular Trap Formation

ABSTRACT

Among preterm infants, bronchopulmonary dysplasia (BPD) is the most prevalent chronic pulmonary disorder. Its pathogenesis involves a complex interplay between prenatal inflammatory exposure and abnormal immune activation. Neutrophil extracellular traps (NETs) are mediators of tissue damage, but whether they bridge intrauterine inflammation and the subsequent development of BPD is not yet clear. We used a prenatal lipopolysaccharide (LPS)‐exposed rat model to ask two questions: first, whether excessive NETs drive BPD pathogenesis, and second, whether human umbilical cord mesenchymal stem cell‐derived microvesicles (hUCMSC‐MVs) can alleviate lung injury by inhibiting this process. We established a BPD model in preterm rats via prenatal LPS exposure and assessed lung morphometry, neutrophil infiltration, and NETs markers. We then compared the therapeutic effects of hUCMSC‐MVs with NET extrusion (NETosis) inhibitors in vivo and also examined direct neutrophil effects in vitro. Prenatal LPS exposure led to significantly elevated NET markers in both lung tissue and circulation, which correlated with severe alveolar simplification. Neutrophils in this model exhibited a “primed” phenotype with enhanced potential for NETs release. In vivo, hUCMSC‐MVs suppressed NET formation, attenuated neutrophilic inflammation, and restored alveolar structure, matching the efficacy of conventional NETosis inhibitors. In vitro, they were internalized by neutrophils and abrogated LPS‐induced NETosis. These findings point to excessive NETosis as a key mechanistic link between prenatal inflammation and postnatal lung impairment. hUCMSC‐MVs directly inhibit this pathological process and alleviate BPD‐like lung injury. This work advances the mechanistic understanding of BPD and supports hUCMSC‐MVs as a promising cell‐free therapeutic candidate.