Mesenchymal stem cell-derived exosomes–a promising therapeutic approach to improve neurocognitive disorders in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is often accompanied by neurocognitive disorders. It seriously affects the quality of life and treatment outcome of patients. COPD-induced neurocognitive disorders (COPD-NCDs) are driven by systemic inflammation, blood-brain barrier (BBB) disruption, and chronic hypoxia, but there is currently no effective treatment to prevent or reverse cognitive decline. Mesenchymal stem cell-derived exosomes (MSC-Exos) are nanoscale extracellular vesicles with unique bioactivity, which have shown great potential in the fields of nervous system diseases, respiratory diseases, bone and joint diseases. Different from traditional cell therapies, MSC-Exos have the advantages of non-immunogenicity, non-tumorigenicity, high stability and biocompatibility. In addition, MSC-Exos can also cross the BBB, regulate neuroinflammation, promote neurogenesis, enhance myelination and improve synaptic plasticity, thereby addressing the multifaceted pathogenesis of central nervous system (CNS) diseases. In this review, we first summarize the pathogenic mechanism of COPD-NCDs, and then summarize the multiple mechanisms of MSC-Exos improving NCDs based on the efficacy of MSC-Exos on other CNS diseases, emphasizing the theoretical basis and unique potential of MSC-Exos as a treatment for COPD-NCDs. Finally, we prospected the future research directions and potential problems of applying MSC-Exos to treat COPD-NCDs, future research should focus on optimizing the large-scale preparation of MSC-Exos, exploring their long-term safety, and advancing clinical translation to address the unmet needs of COPD-NCDs patients.

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that is heterogeneous and often characterized by persistent respiratory symptoms and progressive incompletely reversible airflow limitation [1]. COPD is the third leading cause of death globally, with about 3.23 million deaths per year, causing a huge economic and social burden worldwide [2]. In recent years, numerous studies have demonstrated the occurrence of extrapulmonary comorbidities in COPD, including cardiovascular disease (pulmonary hypertension, coronary artery disease, heart failure, etc.), neurocognitive disorders, anxiety, depression, osteoporosis, nutritional deficiencies, obesity, metabolic complications (metabolic syndrome and diabetes mellitus), and sleep disorders [3–6]. Neurocognitive disorders are found in up to 61% of patients with COPD [7], manifesting as memory loss, impaired executive function, and decreased attention [2]. The high prevalence of neurocognitive disorders in COPD patients (61%) suggests a bidirectional relationship between systemic inflammation and neuronal damage. COPD-induced neurocognitive disorders (COPD-NCDs) reduce treatment compliance, impair pulmonary rehabilitation outcomes, and worsen critical metrics such as quality of life, hospitalization rates and survival, ultimately increasing mortality and disability [5, 7–9]. Poor adherence may stem from impaired memory and executive function, which compromise medication management and rehabilitation participation [10].

The widely accepted etiological theory of COPD-NCDs involves two synergistic pathways. Firstly, systemic inflammation and oxidative stress, hallmarks of COPD, drive extrapulmonary damage through circulating C-reactive protein (CRP), pro-inflammatory cytokines (e.g., interleukin (IL)-6, and tumor necrosis factor-α (TNF-α)) and reactive oxygen species (ROS) [2, 11]. Spillage of these mediators into the somatic circulation compromises the integrity of the blood-brain barrier (BBB), enabling peripheral neurotoxins to penetrate into the brain parenchyma, triggering activation of microglia and astrocytes, and ultimately leading to neuronal damage [2, 12, 13]. Secondly, chronic hypoxia, a consequence of impaired lung function, further exacerbates neuronal injury through mechanisms such as oxidative stress and mitochondrial dysfunction, contributing to the cognitive decline observed in COPD patients.