Hu Liu-Ting, Wang Bing-Yang, Fan Yu-Hua, He Zhi-Yi, Zheng Wen-Xu
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province; Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
Neural Regen Res. 2023 Mar;18(3):560-567. doi: 10.4103/1673-5374.346551.
Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.
我们之前的研究表明，脑出血（ICH）患者中miR-23b表达下调。这表明miR-23b可能与ICH的病理生理机制密切相关，但这一假设缺乏直接证据。在本研究中，我们通过向右侧基底神经节注射Ⅶ型胶原酶建立ICH大鼠模型，并经尾静脉注射骨髓间充质干细胞（BMSC）来源的外泌体miR-23b对其进行治疗。我们发现，与ICH组相比，注射BMSC外泌体miR-23b后大鼠脑内水肿明显减轻，行为改善。此外，外泌体miR-23b被转运至小胶质细胞/巨噬细胞，从而减轻ICH后的氧化应激和细胞焦亡。我们还在体外使用血红素模拟ICH条件。我们发现，第10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）是miR-23b的下游靶基因，外泌体miR-23b通过调节PTEN/Nrf2通路发挥抗氧化作用。此外，miR-23b减少了PTEN与含吡咯结构域的NOD样受体家族成员3（NLRP3）的结合以及NLRP3炎性小体的激活，从而降低了NLRP3依赖性细胞焦亡水平。这些发现表明，BMSC来源的外泌体miR-23b通过抑制PTEN和减轻NLRP3炎性小体介导的细胞焦亡发挥抗氧化作用，从而促进ICH大鼠神经功能恢复。
