Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Neurocognitive Disorders in Chronic Obstructive Pulmonary Disease by Suppressing Neuroinflammation

Background Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from COPD-related neurocognitive disorders (COPD-NCDs), which severely impair their quality of life. Neuroinflammation is a key pathological mechanism, but effective therapies are still lacking. Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) have anti-inflammatory and neuroprotective effects in other neurological disorders. However, their efficacy and underlying mechanisms in COPD-NCDs remain unclear. Methods Female BALB/c mice were divided into normal control (NC), COPD-NCDs (model), COPD-NCDs + PBS (vehicle), and COPD-NCDs + Exos (treatment) groups. COPD-NCDs was induced by 24 weeks of cigarette smoke exposure, and hUCMSC-Exos were administered via tail vein during weeks 20–23. Cognitive function, pulmonary function, lung and hippocampal pathology, microglial activation, astrocytic A1/A2 phenotype, inflammatory cytokines, and hippocampal RNA-seq were assessed. Results hUCMSC-Exos significantly improved lung function, reduced pulmonary inflammation, emphysema, collagen deposition, and systemic inflammation. Importantly, hUCMSC-Exos also improved cognitive function, attenuated hippocampal neuronal damage (increased Nissl-positive neurons and NeuN expression), inhibited microglial activation, and reduced inflammatory cytokine levels in brain tissue. Furthermore, hUCMSC-Exos downregulated the A1 astrocyte marker C3 and upregulated the A2 marker S100A10. RNA-seq suggested modulation of MAPK, Wnt, cAMP and PI3K-Akt signaling pathways. Conclusions hUCMSC-Exos improved cognitive function in COPD-NCDs mice, which was associated with inhibition of microglial activation and a shift from an A1-like to an A2-like astrocytic phenotype. These findings highlight the potential of hUCMSC-Exos as a therapeutic strategy for COPD-NCDs, although the causal relationship between phenotype shift and cognitive improvement requires further mechanistic validation.