ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia
ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia
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ESC-sEVs 通过激活溶酶体来恢复衰老海马 NSCs 以改善血管性痴呆的认知功能
DOI：
10.1002/advs.201903330
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发表时间：
2020-03-20
期刊：
影响因子：
15.1
通讯作者：
Deng, Zhifeng
中科院分区：
文献类型：
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作者：
Hu, Guowen;Xia, Yuguo;Deng, Zhifeng
血管性痴呆(VD)是最常见的痴呆类型之一，但其内在机制尚不清楚，尚缺乏有效的药物治疗。在本研究中，VD大鼠表现出进行性的认知功能障碍，以及与时间相关的海马神经干细胞(H-NSCs)衰老、丢失和神经发生能力下降。然后，将胚胎干细胞来源的小细胞外小泡(ESC-SEV)静脉注射到VD大鼠体内。ESC-SEVS治疗显著缓解H-NSCs的衰老，恢复受损的增殖和神经元分化能力，并逆转认知功能障碍。芯片分析和RT-qPCR结果表明，在ESC-SEV中存在miR-17-5p、miR-18a-5p、miR-21-5p、miR-29a-3p和let-7a-5p等抑制mTORC1活性的miRNAs。ESC-SEV通过转移这些miRNAs抑制mTORC1的激活，促进转录因子EB(TFEB)的核转位和溶酶体的恢复，从而部分地恢复H-NSCs的衰老。综上所述，这些数据表明，在VD中，H-NSCs衰老导致细胞枯竭、神经发生减少和认知功能障碍。ESC-SEVS治疗通过抑制mTORC1的激活，促进TFEB核转位和溶酶体恢复，改善H-NSCs的衰老，从而逆转与衰老相关的神经发生功能障碍和认知功能障碍。ESC-SEV的应用可能为VD患者以及其他与衰老相关的疾病提供一种新的无细胞治疗工具。
Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time-related increasing in hippocampal neural stem cells (H-NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) are intravenously injected into VD rats. ESC-sEVs treatment significantly alleviates H-NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT-qPCR it is identified that several miRNAs including miR-17-5p, miR-18a-5p, miR-21-5p, miR-29a-3p, and let-7a-5p, that can inhibit mTORC1 activation, exist in ESC-sEVs. ESC-sEVs rejuvenate H-NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H-NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC-sEVs treatment ameliorates H-NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence-related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC-sEVs may be a novel cell-free therapeutic tool for patients with VD, as well as other aging-related diseases.