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MSC-small extracellular vesicles alleviated Th2-airway inflammation by regulating the metabolism of DCs in mice

ABSTRACT: Background: Allergic asthma is one of the chronic inflammatory diseases and is generally induced by CD4+ T helper 2 cells (Th2) in the context of persistent inhaled stimuli. Dendritic cells (DCs) are essential to mounting the Th2-mediated airway inflammation by presenting inhaled antigens to prime CD4+ T cells. Small extracellular vesicles (sEV) derived from mesenchymal stem cells (MSCs) exhibited great interest in intractable diseases. However, whether MSC-sEV play a role on DCs in airway inflammation is still unclear. Methods: We isolate MSC-sEV using anion-exchange chromatography. Mouse bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs) were used to study the effects of MSC-sEV on dendritic cell surface molecules and their cytokine release. Mice were sensitized with house dust mites (HDM) to induce airway inflammation, and treated with MSC-sEV, The effects of sEV on murine DCs were identified. Extracellular flux analysis techniques were used to study the effects of MSC-sEV on the metabolic state of dendritic cells. RNA sequencing to study altered gene expression in BMDCs after MSC-sEV treatment. Results: MSC-sEV mitigated the accumulation of Th2-associated moDCs in mouse lung in response to HDM. MSC-sEV also decreased the activation of moDCs induced in vitro including the expression of co-stimulatory molecules and cytokines secretion. Furthermore, we identified that DCs were able to take MSC-sEV in vitro and in vivo. Mechanistically, using bulk RNA-sequencing, we found that MSC-sEV played roles in the metabolic pathway of murine DCs. Using extracellular flux analysis, we found that MSC-sEV increased the requirement of oxidative phosphorylation on moDCs. Importantly, MSC-sEV displayed similar effects on human moDCs including decreased co-stimulatory molecular and cytokine production. Conclusions: MSC-sEV are able to alter the metabolic state of DCs, favoring DCs to maintain OXPHOS (oxidative phosphorylation) rather than glycolysis, thereby reducing DCs-initiated inflammatory responses and attenuating Th2 lung inflammation, suggesting MSC-sEV can be a potential clinical therapy for airway inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE268139 | GEO | 2024/05/23

REPOSITORIES: GEO

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Project description:The beneficial effects of mesenchymal stem cell administration have been reported in numerous preclinical studies. Briefly, decreased levels of Th2-related cytokines, namely IL-4, IL-5, and IL-13, impaired eosinophils infiltration, and mucus secretion within the lung have been recognized as hallmarks of MSC-mediated immunosuppression in OVA-Alumn- induced experimental model. However, to date, the effects of MSCs transfer on mixed airway inflammation remain elusive. Therefore, here we aimed to investigate the influence of internasal adipose tissue-derived MSCs on mixed inflammation in a house dust mite (HDM) extract-induced experimental asthma model. To induce mixed airway inflammation, mice were challenged with 10 g of HDM extract for 5 days each week. Additionally, to investigate the short- and long-term effects, adipose tissue-derived MSCs were administrated at two-time points. To analyze MSC-mediated changes, we assessed lung morphology, frequencies of T cells effectors, epithelial barrier integrity, lung transcriptomic profiles, and the levels of cytokines and chemokine in bronchoalveolar lavage (BAL). We observed the limitation of cellular infiltration and mucus production after MSCs administration. Moreover, we noted a trend to decrease in the frequencies of T cells producing IL-4 and IFNy as a long-term effect of MSCs administration. Additionally, the expression of ZO-1 was increased in both analyzed time-points of MSCs transfer. Notably, we found the changes in the transcriptomic profiles reflecting, the inflammation of the respiratory system, the proliferation of lymphocytes, migration of leukocytes, and recruitment of neutrophils and eosinophils. Finally, we also noted the differences in the levels of CXCL and CCL chemokines in BAL between short- and long-term models, while the changes in Th2-related cytokines levels were limited. Overall, here we confirmed the therapeutic potential of adipose tissue-derived MSCs administration in a novel HDM extract-induced experimental model of mixed airway inflammation.

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MSC-small extracellular vesicles alleviated Th2-airway inflammation by regulating the metabolism of DCs in mice

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