Mesenchymal stem cells (MSCs) have been used in clinical studies to treat neurological diseases and damage. However, implanted MSCs do not achieve their regenerative effects by differentiating into and replacing neural cells. Instead, MSC secretome components mediate the regenerative effects of MSCs. MSC-derived extracellular vesicles (EVs)/exosomes carry cargo responsible for rescuing brain damage. We previously showed that EP4 antagonist-induced MSC EVs/exosomes have enhanced regenerative potential to rescue hippocampal damage, compared with EVs/exosomes from untreated MSCs. Here we show that EP4 antagonist-induced MSC EVs/exosomes promote neurosphere formation in vitro and increase neurogenesis and neuritogenesis in damaged hippocampi; basal MSC EVs/exosomes do not contribute to these regenerative effects. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) levels in EP4 antagonist-induced MSC EVs/exosomes are 20-fold higher than CNP levels in basal MSC EVs/exosomes. Decreasing elevated exosomal CNP levels in EP4 antagonist-induced MSC EVs/exosomes reduced the efficacy of these EVs/exosomes in promoting β3-tubulin polymerization and in converting toxic 2',3'-cAMP into neuroprotective adenosine. CNP-depleted EP4 antagonist-induced MSC EVs/exosomes lost the ability to promote neurogenesis and neuritogenesis in damaged hippocampi. Systemic administration of EV/exosomes from EP4 -antagonist derived MSC EVs/exosomes repaired cognition, learning, and memory deficiencies in mice caused by hippocampal damage. In contrast, CNP-depleted EP4 antagonist-induced MSC EVs/exosomes failed to repair this damage. Exosomal CNP contributes to the ability of EP4 antagonist-elicited MSC EVs/exosomes to promote neurogenesis and neuritogenesis in damaged hippocampi and recovery of cognition, memory, and learning. This experimental approach should be generally applicable to identifying the role of EV/exosomal components in eliciting a variety of biological responses.

译文

间充质干细胞 (MSCs) 已被用于治疗神经系统疾病和损伤的临床研究。然而,植入的MSCs不能通过分化和替代神经细胞来实现其再生效果。相反,MSC分泌组成分介导了MSC的再生效应。MSC衍生的细胞外囊泡 (EVs)/外泌体携带负责抢救脑损伤的货物。我们先前表明,与未经治疗的MSCs/exosomes相比,EP4拮抗剂诱导的MSC EVs/exosomes具有增强的再生潜力来挽救海马损伤。在这里,我们显示EP4拮抗剂诱导的MSC EVs/外泌体在体外促进神经球形成,并增加受损海马的神经发生和神经发生; 基础MSC EVs/外泌体对这些再生作用没有贡献。EP4拮抗剂诱导的MSC EVs/外泌体中的2 ',3'-环核苷酸3 '-磷酸二酯酶 (CNP) 水平比基础MSC EVs/外泌体中的CNP水平高20倍。降低EP4拮抗剂诱导的MSC EVs/exosome中的exosome CNP水平升高会降低这些EVs/exosome在促进 β3-微管蛋白聚合和将有毒的2 ',3'-cAMP转化为神经保护性腺苷方面的功效。CNP耗尽的EP4拮抗剂诱导的MSC EVs/外泌体失去了促进受损海马神经发生和神经发生的能力。从EP4拮抗剂衍生的MSC EVs/exosomes全身施用EV/exosomes可修复由海马损伤引起的小鼠的认知,学习和记忆缺陷。相反,CNP耗尽的EP4拮抗剂诱导的MSC EVs/外泌体无法修复这种损伤。外泌体CNP有助于EP4拮抗剂引发的MSC EVs/外泌体促进受损海马神经发生和神经发生以及认知,记忆和学习恢复的能力。这种实验方法通常应适用于确定EV/外源体成分在引起各种生物学反应中的作用。

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