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干细胞移植可增强脑卒中大脑中内源性细胞外囊泡的表达。

Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain.

机构信息

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States.

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States.

出版信息

Brain Res Bull. 2024 Aug;214:110999. doi: 10.1016/j.brainresbull.2024.110999. Epub 2024 Jun 6.

Abstract

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.

摘要

内源性脑修复发生在缺血性中风后,但这种修复是短暂的,因此无法完全产生针对不断发展的继发性细胞死亡的神经保护反应。寻找一种可能产生强大而持久治疗效果的治疗策略,是中风临床相关治疗的一个重要目标。中风后细胞外囊泡似乎会被上调,这可能代表神经保护的候选靶点。在这项研究中,我们探讨了移植的干细胞是否可以增强细胞外囊泡的表达,从而为缺血性中风大脑提供稳定的组织重塑。首先,老年大鼠暴露于大脑中动脉闭塞的既定缺血性中风模型中,然后接受骨髓间充质干细胞移植或载体的静脉内递送。一年后,对动物进行脑损伤、炎症和细胞外囊泡表达的检测。我们的研究结果表明,虽然核心梗死没有减少,但接受干细胞移植的中风动物显示出梗死周围细胞丢失的显著减少,这与 Iba1 标记的炎症细胞下调和 CD63 阳性细胞外囊泡上调相一致,这些囊泡似乎与 GFAP 阳性星形胶质细胞共定位。有趣的是,在移植后一年没有检测到移植的干细胞,这表明这些细胞外囊泡可能来源于宿主大脑。在没有存活的移植干细胞的情况下,这种持久的功能益处仍然存在,但伴随着内源性细胞外囊泡的上调,这一发现表明,中风后急性移植干细胞会促使宿主细胞外囊泡进入缺血性大脑,共同促进慢性大脑重塑。

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