ABSTRACT

Mesenchymal stem cell transplantation (MSCT) has been applied to treat a variety of autoimmune and inflammatory diseases. Psychosocial stress can aggravate disease progression in chronic inflammatory patients. Whether psychological stress affects MSCT is largely unknown. In this study we show that psychological stress attenuates therapeutic effects of MSCT in a DSS-induced colitis mouse model by elevating the levels of exosomal Mir7k/mmu-let-7 k (microRNA 7 k) in circulation. Mechanistically, Mir7k inhibits STAT3 pathway in donor MSCs, leading to upregulated expression of BECN1 (beclin 1, autophagy related) and, thus, activation of macroautophagy/autophagy. Inhibition of autophagy by blocking Mir7k or activating STAT3 signaling can restore MSCT-mediated therapy in psychologically stressed colitis mice. Our study identifies a previously unknown role of autophagy in regulating MSCT therapy via exosomal miRNA Mir7k.

Abbreviations: BafA1: bafilomycin A₁; BECN1: beclin 1, autophagy related; DAI: disease activity index; DAPI: 4ʹ,6-diamidino-2-phenylindole; DSS: dextran sulfate sodium; GFP: green fluorescent protein; HAI: histological activity index; IFNG/IFN-γ: interferon gamma; IL10: interleukin 10; IL1RN/IL-1Rra: interleukin 1 receptor antagonist; KD: knockdown; miRNA: microRNA; MSCs: mesenchymal stem cells; MSCT: mesenchymal stem cell transplantation; NTA: nanoparticle tracking analysis; PGE2: prostaglandin E2; SD: standard deviation; siRNA: small-interfering RNA; STAT3: signal transducer and activator of transcription 3; TEM: transmission electron microscopy; TGFB1/TGF-β1: transforming growth factor, beta 1; Th17 cell: T helper cell 17; TNF/TNF-α: tumor necrosis factor; TNFAIP6/TSG6: tumor necrosis factor alpha induced protein 6; Tregs: regulatory T cells

摘要

间充质干细胞移植（MSCT）已被应用于治疗多种自身免疫性疾病和炎症性疾病。社会心理压力会加剧慢性炎症患者的疾病进展。心理压力是否会影响 MSCT 在很大程度上是未知的。在这项研究中，我们表明心理压力通过提高循环中外泌体Mir7k/mmu-let-7 k (microRNA 7 k) 的水平来减弱 MSCT 在 DSS 诱导的结肠炎小鼠模型中的治疗效果。从机制上讲，Mir7k抑制供体 MSC 中的 STAT3 通路，导致 BECN1（beclin 1，自噬相关）的表达上调，从而激活巨自噬/自噬。通过阻断Mir7k抑制自噬或激活 STAT3 信号可以恢复 MSCT 介导的心理应激结肠炎小鼠治疗。我们的研究确定了自噬在通过外泌体 miRNA Mir7k调节 MSCT 治疗中的未知作用。

缩写： BafA1：巴弗洛霉素 A ₁; BECN1：beclin 1，自噬相关；DAI：疾病活动指数；DAPI：4ʹ,6-二脒基-2-苯基吲哚；DSS：硫酸葡聚糖钠；GFP：绿色荧光蛋白；HAI：组织学活动指数；IFNG/IFN-γ：干扰素γ；IL10：白细胞介素 10；IL1RN/IL-1Rra：白细胞介素 1 受体拮抗剂；KD：击倒；miRNA：微小RNA；MSCs：间充质干细胞；MSCT：间充质干细胞移植；NTA：纳米粒子跟踪分析；PGE2：前列腺素 E2；SD：标准差；siRNA：小干扰RNA；STAT3：信号转导和转录激活因子 3；TEM：透射电子显微镜；TGFB1/TGF-β1：转化生长因子，β1；Th17细胞：T辅助细胞17；TNF/TNF-α：肿瘤坏死因子；TNFAIP6/TSG6：肿瘤坏死因子α诱导蛋白6；Tregs：调节性 T 细胞