Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25.
Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25.
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脂肪衍生的间充质干细胞通过miR-25的细胞外囊泡转移减少了中风小鼠的自噬。
DOI：
10.1002/jev2.12024
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发表时间：
2020-10
影响因子：
16
通讯作者：
Doeppner TR
中科院分区：
文献类型：
--
作者：
Kuang Y;Zheng X;Zhang L;Ai X;Venkataramani V;Kilic E;Hermann DM;Majid A;Bähr M;Doeppner TR
移植间充质干细胞（MSC）通过分泌细胞外囊泡（EV）在临床前中风模型中产生神经保护作用。然而，电动汽车的神经保护作用尚未确定。为了研究这些货物及其潜在机制，将原代神经元暴露于氧葡萄糖剥夺（OGD）并与脂肪源性间充质干细胞（ADMSC）或ADMSC分泌的EV共培养。在这种条件下，ADMSC 和 ADMSC 分泌的 EV 均显着减少了神经元死亡。对参与 ADMSC 和神经元之间相互作用的信号级联的筛选显示，接受任一治疗模式的神经元中自噬通量减少以及 p53-BNIP3 活性下降。然而，当 ADMSCs 用外泌体分泌抑制剂 GW4869 预处理或 Hrs 被敲低时，上述效果就会逆转。鉴于 miR-25-3p 是 ADMSC-EV 中与 p53 通路相互作用的最高表达的 miRNA，进一步的体外工作集中在该通路上。事实上，miR-25-3p 寡核苷酸模拟物减少了细胞死亡，而抗寡核苷酸通过调节暴露于 OGD 的原代神经元中的 p53-BNIP3 信号传导来增加自噬通量和细胞死亡。同样，天然 ADMSC-EV，而不是从用抗 miR-25-3p 寡核苷酸（ADMSC-EVsanti-miR-25-3p）预处理的 ADMSC 中获得的 EV，证实了暴露于脑缺血的 C57BL/6 小鼠中的上述体外观察结果。与 ADMSC-EVsanti-miR-25-3p 相比，用天然 ADMSC-EV 治疗的小鼠梗塞面积减小，神经功能恢复增加。 ADMSC 通过分泌含有 miR-25-3p 的 EV 来改善自噬通量，从而诱导神经保护。因此，我们的工作揭示了自然分泌的 ADMSC-EV 中的一个新的关键因素，用于在临床前中风模型中调节自噬和诱导神经保护。
Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen‐glucose‐deprivation (OGD) and cocultured with adipose‐derived MSCs (ADMSCs) or ADMSC‐secreted EVs. Under such conditions, both ADMSCs and ADMSC‐secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53‐BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR‐25‐3p being the most highly expressed miRNA in ADMSC‐EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR‐25‐3p oligonucleotide mimic reduced cell death, whereas the anti‐oligonucleotide increased autophagic flux and cell death by modulating p53‐BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC‐EVs but not EVs obtained from ADMSCs pretreated with the anti‐miR‐25‐3p oligonucleotide (ADMSC‐EVsanti‐miR‐25‐3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC‐EVs when compared to ADMSC‐EVsanti‐miR‐25‐3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR‐25‐3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC‐EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.
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影响因子：
6.3
作者：
Doeppner, Thorsten R.;Nagel, Florian;Baehr, Mathias
通讯作者：
Baehr, Mathias
影响因子：
6.3
作者：
Doeppner, Thorsten R.;Kaltwasser, Britta;Baehr, Mathias
通讯作者：
Baehr, Mathias
影响因子：
16
作者：
Freitas, Daniela;Balmana, Meritxell;Reis, Celso A.
通讯作者：
Reis, Celso A.
影响因子：
6
作者：
Doeppner, Thorsten R.;Herz, Josephine;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
影响因子：
2.7
作者：
Baraniak PR;McDevitt TC
通讯作者：
McDevitt TC