Human umbilical cord mesenchymal stem cell-derived exosomes alleviate neurocognitive disorders in chronic obstructive pulmonary disease by suppressing neuroinflammation

Abstract 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. Pulmonary function, cognitive function, lung and hippocampal pathology, microglial activation, inflammatory cytokines, astrocytic A1/A2 phenotype, and brain RNA-seq were assessed. Results hUCMSC-Exos significantly improved lung function in COPD-NCDs mice and alleviated pulmonary inflammation, emphysema, collagen deposition, and systemic inflammation. Importantly, hUCMSC-Exos also ameliorated cognitive impairment in COPD-NCDs mice, alleviated hippocampal neuronal damage (increased Nissl-positive neurons and NeuN expression), suppressed microglial activation, and reduced the levels of inflammatory cytokines in brain tissue. Furthermore, hUCMSC-Exos downregulated C3, a marker of type A1 neurotoxic astrocytes, and upregulated S100A10, a marker of type A2 neuroprotective astrocytes, in the hippocampus of COPD-NCDs mice. RNA-seq suggested modulation of MAPK, Wnt, cAMP and PI3K-Akt signaling pathways. Conclusions hUCMSC-Exos ameliorated cognitive impairment in COPD-NCDs mice, which may be associated with the suppression of microglial activation and the shift in astrocyte phenotype from A1-like to A2-like. These findings highlight the potential of hUCMSC-Exos as a therapeutic strategy for COPD-NCDs, although the causal relationship between the phenotypic shift and cognitive improvement requires further mechanistic validation.