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Cell-Free Extracellular Vesicles Derived from Human Bone Marrow Endothelial Progenitor Cells as Potential Therapeutics for Microvascular Endothelium Restoration in ALS.
NeuroMolecular Medicine ( IF 3.3 ) Pub Date : 2020-08-20 , DOI: 10.1007/s12017-020-08607-1
Svitlana Garbuzova-Davis 1, 2, 3, 4 , Alison E Willing 1, 2, 3 , Jared Ehrhart 1 , Lianchun Wang 5 , Paul R Sanberg 1, 2, 4, 6 , Cesario V Borlongan 1, 2
Affiliation  

Repairing the damaged blood-CNS-barrier in amyotrophic lateral sclerosis (ALS) is necessary to prevent entry of detrimental blood-borne factors contributing to motor neuron dysfunction. Recently, we showed benefits of human bone marrow endothelial progenitor cell (hBM-EPC) transplantation into symptomatic ALS mice on barrier restoration by replacing damaged endothelial cells (ECs). Additionally, transplanted cells may endogenously repair ECs by secreting angiogenic factors as our subsequent in vitro study demonstrated. Based on these study results, hBM-EPCs may secrete extracellular vesicles, which may contain and transfer diverse vesicular biomolecules towards maintenance of EC functionality. The study aimed to characterize extracellular vesicles (EVs) derived from hBM-EPCs as potential cell-free therapeutics for endothelium repair in ALS. EVs were isolated from hBM-EPC media at different culture times and vesicle properties were evaluated. The protective effects of EVs on mouse brain endothelial cells (mBECs) exposed to ALS mouse plasma were investigated. Uptake and blockage of EVs from GFP-transfected hBM-EPCs in ECs were determined in vitro. Results showed that EVs isolated from hBM-EPCs as nanosized vesicles significantly reduced mBEC damage from the pathological environment and these EVs were taken up by cells. Blockage of β1 integrin on EVs prevented internalization of vesicles in mBECs. Together, these results provide evidence for potential of hBM-EPC-derived EVs as novel cell-free therapeutics for repair of endothelium in ALS. Although determining translational potential of hBM-EPC-derived EVs will require evaluation in vivo, this in vitro study represents a step towards an extracellular vesicle-based approach for repair of the damaged microvascular endothelium in ALS.



中文翻译:

源自人骨髓内皮祖细胞的无细胞细胞外囊泡作为 ALS 微血管内皮恢复的潜在治疗方法。

修复肌萎缩侧索硬化症 (ALS) 中受损的血液中枢神经系统屏障对于防止导致运动神经元功能障碍的有害血源因子进入是必要的。最近,我们展示了将人骨髓内皮祖细胞(hBM-EPC)移植到有症状的 ALS 小鼠体内,通过替换受损的内皮细胞(EC)来恢复屏障的益处。此外,正如我们随后的体外研究所证明的那样,移植细胞可以通过分泌血管生成因子来内源性修复 EC。基于这些研究结果,hBM-EPCs 可能会分泌细胞外囊泡,其中可能包含并转移多种囊泡生物分子以维持 EC 功能。该研究旨在表征源自 hBM-EPC 的细胞外囊泡(EV)作为 ALS 内皮修复的潜在无细胞疗法。在不同培养时间从 hBM-EPC 培养基中分离出 EV,并评估囊泡特性。研究了 EV 对暴露于 ALS 小鼠血浆的小鼠脑内皮细胞 (mBEC) 的保护作用。体外测定 EC 中 GFP 转染的 hBM-EPC 对 EV 的摄取和阻断。结果表明,从 hBM-EPC 中分离出的 EV 作为纳米级囊泡显着减少了病理环境对 mBEC 的损伤,并且这些 EV 被细胞吸收。阻断 EV 上的 β1 整合素可阻止 mBEC 中囊泡的内化。总之,这些结果为 hBM-EPC 衍生的 EV 作为新型无细胞疗法修复 ALS 内皮细胞的潜力提供了证据。尽管确定 hBM-EPC 衍生的 EV 的转化潜力需要进行体内评估,

更新日期:2020-08-20
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