人血小板浓缩上清液细胞外囊泡对创伤性脑损伤和帕金森病模型的神经保护作用。

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-09-05 DOI:10.1186/s12929-024-01072-z
Liling Delila, Ouada Nebie, Nhi Thao Ngoc Le, Kelly Timmerman, Deng-Yao Lee, Yu-Wen Wu, Ming-Li Chou, Luc Buée, Szu-Yi Chou, David Blum, David Devos, Thierry Burnouf
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引用次数: 0

摘要

背景:再生医学领域正在蓬勃发展,最近关于使用从临床级血小板浓缩物(PCs)中提取的人血小板裂解物(HPLs)治疗脑部疾病的生物疗法的研究结果大大推进了这一领域的发展。这些进展为探索血小板胞外囊泡(PEVs)的神经保护作用开辟了新的转化研究途径。它们在治疗创伤性脑损伤(TBI)和帕金森病(PD)等神经退行性疾病方面的潜力值得进一步探索。我们在此旨在描述从血小板浓缩物(PC)上清液中分离出的 PEV 制剂的组成,并确定其在创伤性脑损伤和帕金森病的细胞和动物模型中的神经保护潜力和神经恢复作用:我们利用高速离心法从健康献血者的临床级 PC 上清液中分离出 PEVs。我们采用生物物理、生物化学、显微镜和 LC-MS/MS 蛋白质组学方法对 PEVs 进行了表征,以揭示其生物功能。在体外,使用 SH-SY5Y 神经元细胞、LUHMES 多巴胺能神经元和 BV-2 小胶质细胞评估了 PEV 的功能;在体内,通过鼻内给药,使用 8 周大的雄性 C57/BL6 小鼠在受控皮质冲击(CCI)-TBI 模型中,以及使用 5 个月大的雄性 C57/BL6 小鼠在 MPTP 诱导的 PD 模型中评估了 PEV 的功能:PEV的大小从50到350纳米不等,主要在200纳米左右,浓度在1010到1011/毫升之间。它们表达特定的血小板膜标记物,在冷冻电镜下显示出脂质双分子层,重要的是,促凝血剂磷脂酰丝氨酸的表达量较低。LC-MS/MS显示了丰富的营养因子成分,包括神经营养素、抗炎剂、神经递质和抗氧化剂,揭示了其多方面的生物功能。PEVs有助于恢复SH-SY5Y细胞的神经元功能,并对麦拉宁诱导的多巴胺能神经元铁突变表现出显著的神经保护能力。在小胶质细胞中,它们能促进抗炎反应,尤其是在炎症条件下。在体内,经鼻给药的PEVs在创伤性脑损伤小鼠模型中显示出强大的抗炎作用,并在帕金森病模型中保持了黑质多巴胺能神经元的酪氨酸羟化酶表达,从而改善了运动功能:基于 PEV 的疗法在神经保护方面的潜力为神经退行性疾病开辟了新的治疗途径。该研究提倡进行临床试验,以确定基于 PEV 的生物疗法在神经再生医学中的疗效。
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Neuroprotective effects of intranasal extracellular vesicles from human platelet concentrates supernatants in traumatic brain injury and Parkinson's disease models.

Background: The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD.

Methods: We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC-MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice.

Results: PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 1010 and 1011/mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC-MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo, intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function.

Conclusions: The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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