Niu Xinyu, Xia Yuguo, Luo Lei, Chen Yu, Yuan Ji, Zhang Juntao, Zheng Xianyou, Li Qing, Deng Zhifeng, Wang Yang
Department of Neurosurgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Department of Neurosurgery; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Mater Today Bio. 2023 Mar 4;19:100600. doi: 10.1016/j.mtbio.2023.100600. eCollection 2023 Apr.
The polarization of microglia plays an important role in the outcome of ischemic stroke (IS). In the aged population, senescent microglia show a predominant pro-inflammatory phenotype, which leads to worse outcomes in aged ischemic stroke compared to young ischemic stroke. Recent research demonstrated that inducible pluripotent stem cell-derived small extracellular vesicles (iPSC-sEVs) possess the significant anti-ageing ability. We hypothesized that iPSC-sEVs could alleviate microglia senescence to regulate microglia polarization in aged ischemic stroke. In this study, we showed that treatment with iPSC-sEVs significantly alleviated microglia senescence as indicated by the decreased senescence-associated proteins including P16, P21, P53, and γ-H2AX as well as the activity of SA-β-gal, and inhibited pro-inflammatory activation of microglia both and in vitro. Furthermore, iPSC-sEVs shifted microglia from pro-inflammatory phenotype to anti-inflammatory phenotype, which reduced the apoptosis of neurons, and improved the outcome of aged stroke mice. Mechanism studies showed that iPSC-sEVs reversed the loss of Rictor and downstream p-AKT (s473) in senescent microglia, which was involved in the senescence and pro-inflammatory phenotype regulation of microglia. Inhibition of Rictor abolished the iPSC-sEVs-afforded phosphorylation of AKT and alleviation of inflammation of senescent microglia. Proteomics results indicated that iPSC-sEVs carried transforming growth factor-β1 (TGF-β1) to upregulate Rictor and p-AKT in senescent microglia, which could be hindered by blocking TGF-β1. Taken together, our work demonstrates iPSC-sEVs reverse the senescent characteristic of microglia in aged brains and therefore improve the outcome after stroke, at least, via delivering TGF-β1 to upregulate Rictor and p-AKT. Our data suggest that iPSC-sEVs might be a novelty therapeutic method for aged ischemic stroke and other diseases involving senescent microglia.
小胶质细胞的极化在缺血性中风（IS）的转归中起重要作用。在老年人群中，衰老的小胶质细胞呈现出主要的促炎表型，这导致老年缺血性中风的预后比年轻缺血性中风更差。最近的研究表明，诱导多能干细胞衍生的小细胞外囊泡（iPSC-sEVs）具有显著的抗衰老能力。我们假设iPSC-sEVs可以减轻小胶质细胞衰老，从而调节老年缺血性中风中小胶质细胞的极化。在本研究中，我们发现用iPSC-sEVs处理可显著减轻小胶质细胞衰老，表现为衰老相关蛋白P16、P21、P53和γ-H2AX减少以及SA-β-半乳糖苷酶活性降低，并且在体内和体外均抑制了小胶质细胞的促炎激活。此外，iPSC-sEVs使小胶质细胞从促炎表型转变为抗炎表型，这减少了神经元的凋亡，并改善了老年中风小鼠的预后。机制研究表明，iPSC-sEVs逆转了衰老小胶质细胞中Rictor和下游p-AKT（s473）的缺失，这与小胶质细胞的衰老和促炎表型调节有关。抑制Rictor消除了iPSC-sEVs介导的AKT磷酸化以及衰老小胶质细胞炎症的减轻。蛋白质组学结果表明，iPSC-sEVs携带转化生长因子-β1（TGF-β1）以上调衰老小胶质细胞中的Rictor和p-AKT，而这可通过阻断TGF-β1来阻碍。综上所述，我们的工作表明iPSC-sEVs可逆转老年大脑中小胶质细胞的衰老特征，从而至少通过递送TGF-β1上调Rictor和p-AKT来改善中风后的预后。我们的数据表明，iPSC-sEVs可能是老年缺血性中风和其他涉及衰老小胶质细胞的疾病的一种新型治疗方法。
