Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China.
Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
Stem Cell Res Ther. 2023 Jul 24;14(1):180. doi: 10.1186/s13287-023-03408-2.
Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs.
Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems.
sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs.
We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.
间充质基质细胞衍生的小细胞外囊泡（MSC-sEVs）因其在各种免疫疾病中的治疗潜力而受到广泛关注。我们之前报道过，MSC-sEVs 通过调节 2 型固有淋巴细胞（ILC2）和树突状细胞（DC）的功能，在过敏性气道炎症中发挥免疫调节作用。因此，本研究旨在通过 DC 研究 MSC-sEVs 对过敏性鼻炎（AR）患者 ILC2 的间接作用。
在此，我们使用阴离子交换色谱从诱导多能干细胞-MSCs 中分离 sEVs，并对成熟 DC（mDCs）进行处理。sEV-mDCs 与 AR 患者的外周血单个核细胞或纯化的 ILC2 共培养。通过流式细胞术检测 ILC2 中 IL-13 和 GATA3 的水平。对 mDCs 和 sEV-mDCs 的总 RNA 序列进行分析，以进一步探讨潜在机制，并在共培养系统中进行验证。
与 mDCs 相比，sEV-mDCs 显示出在启动 ILC2 中 IL-13 和 GATA3 水平方面的能力受损。此外，sEV-mDCs 产生更高水平的 PGE2 和 IL-10，阻断这些细胞因子特别是前者可以逆转 sEV-mDCs 的抑制作用。
我们证明了 MSC-sEVs 能够抑制 AR 患者 mDCs 对 ILC2 的激活作用。机制上，PGE2-EP2/4 轴在 sEV-mDCs 对 ILC2 的免疫调节作用中发挥了重要作用。本研究为 MSC-sEVs 在过敏性气道炎症治疗中的作用机制提供了新的见解。
