Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression
Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression
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DOI：
10.5966/sctm.2015-0078
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发表时间：
2015-10-01
影响因子：
6
通讯作者：
Hermann, Dirk M.
中科院分区：
文献类型：
--
作者：
Doeppner, Thorsten R.;Herz, Josephine;Hermann, Dirk M.
虽然干细胞治疗的最初概念旨在替换丢失的组织，但最近的证据表明，干细胞和祖细胞都能通过分泌恢复受损大脑重塑能力的因子来促进缺血后神经恢复。具体而言，最近已经提出来源于干细胞的细胞外囊泡（EV）如外来体介导恢复性干细胞效应。为了确定EV是否确实改善缺血后神经功能缺损和脑重塑，我们系统地比较了间充质干细胞（MSC）衍生的EV（MSC-EV）与在C57BL6小鼠局灶性脑缺血后第1天，第3天和第5天（MSC-EV）或第1天（MSC）静脉内递送给小鼠的MSC的作用。在中风后长达28天的时间里，分析了运动协调缺陷、组织学脑损伤、外周血和脑中的免疫反应以及脑血管生成和神经发生。在接受来自两种不同骨髓来源的MSC谱系的EV的中风小鼠中，注意到与增强的血管神经发生相关的神经损伤和长期神经保护的改善。MSC-EV给药与MSC的反应非常相似，并在整个观察期间持续存在。虽然脑免疫细胞浸润不受MSC-EV的影响，但缺血后免疫抑制（即，B细胞、自然杀伤细胞和T细胞淋巴细胞减少症）在缺血后6天在外周血中减弱，为成功的脑重塑提供了适当的外部环境。由于MSC-EV最近被证明在人类中是明显安全的，因此本研究提供了临床相关证据，支持在中风患者中进行快速概念验证研究。干细胞翻译医学2015; 4：1131 - 1143
Although the initial concepts of stem cell therapy aimed at replacing lost tissue, more recent evidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain's capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects. In order to define whether EVs indeed improve postischemic neurological impairment and brain remodeling, we systematically compared the effects of mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) with MSCs that were i.v. delivered to mice on days 1, 3, and 5 (MSC-EVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral blood and brain, and cerebral angiogenesis and neurogenesis were analyzed. Improved neurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1131-1143