脐带血衍生的外泌体减轻帕金森病小鼠模型中多巴胺能神经元的损伤。
Umbilical cord blood-derived exosomes attenuate dopaminergic neuron damage of Parkinson's disease mouse model.
机构信息
Research Center for Translational Medicine, Department of Anesthesiology, Department of Obstetrics, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei Provincial Clinical Research Center for Parkinson's Disease at Xiangyang No.1 People's Hospital, Hubei University of Medicine, 15 Jiefang Road, Xiangyang, 441000, China.
Clinical Laboratory, Wuhan Asia Heart Hospital, Wuhan, 430022, China.
出版信息
J Nanobiotechnology. 2024 Sep 14;22(1):567. doi: 10.1186/s12951-024-02773-1.
BACKGROUND
Umbilical cord blood (UCB) is a rich source of multifunctional stem cells characterized by low immunogenicity. Recent research in the fields of aging and regenerative medicine has revealed the potential of human umbilical cord blood-derived exosomes (UCB-Exos) in promoting wound healing, anti-aging, and regeneration. However, their role in neurodegenerative diseases, specifically Parkinson's disease (PD), remains unexplored. This study investigates the potential therapeutic effects and underlying mechanisms of UCB-Exos on PD.
METHODS
Large extracellular vesicles (LEv), Exos, and soluble fractions (SF) of human UCB plasma were extracted to investigate their effects on motor dysfunction of the MPTP-induced PD mouse model and identify the key components that improve PD symptoms. UCB-Exos were administered by the caudal vein to prevent or treat the PD mouse model. The motor function and pathological markers were detected. Differentially expressed gene and KEGG enrichment pathways were screened by transcriptome sequence. MN9D and SH-SY5Y cells were cultured and evaluated for cell viability, oxidative stress, cell cycle, and aging-related indexes by qRT-PCR, western blot, immunofluorescence, and flow cytometry. The protein expression level of the MAPK p38 and ERK1/2 signaling pathway was detected by western blot.
RESULTS
We observed that LEv, Exos, and SF all exhibited potential in ameliorating motor dysfunction in MPTP-induced PD model mice, with UCB-Exos demonstrating the most significant effect. UCB-Exos showed comparable efficacy in preventing and treating motor dysfunction, cognitive decline, and substantia nigra pathological damage in PD mice. Further investigations revealed that UCB-Exos could potentially alleviate oxidative damage, aging and degeneration, and energy metabolism disorders in neurons. Transcriptome sequencing results corroborated that genes differentially expressed due to UCB-Exos were primarily enriched in the neuroactive ligand-receptor interaction, Dopaminergic synapse, and MAPK signaling pathway. We also observed that UCB-Exos significantly inhibited the hyperphosphorylation of the MAPK p38 and ERK1/2 signaling pathways both in vitro and in vivo.
CONCLUSIONS
Our study provides a comprehensive evaluation of UCB-Exos on the neuroprotective effects and suggests that inhibition of hyperphosphorylation of MAPK p38 and ERK 1/2 signaling pathways by regulating transcription levels of HspB1 and Ppef2 may be the key mechanism for UCB-Exos to improve PD-related pathological features.
背景
脐带血（UCB）是一种富含多功能干细胞的丰富来源，其特点是免疫原性低。衰老和再生医学领域的最新研究揭示了人脐带血衍生外泌体（UCB-Exos）在促进伤口愈合、抗衰老和再生方面的潜力。然而，它们在神经退行性疾病，特别是帕金森病（PD）中的作用仍未得到探索。本研究探讨了 UCB-Exos 对 PD 的潜在治疗效果和潜在机制。
方法
提取人 UCB 血浆中的大细胞外囊泡（LEv）、Exos 和可溶性部分（SF），以研究它们对 MPTP 诱导的 PD 小鼠模型运动功能障碍的影响，并确定改善 PD 症状的关键成分。通过尾静脉给予 UCB-Exos 以预防或治疗 PD 小鼠模型。检测运动功能和病理标志物。通过转录组序列筛选差异表达基因和 KEGG 富集途径。培养 MN9D 和 SH-SY5Y 细胞，通过 qRT-PCR、western blot、免疫荧光和流式细胞术评估细胞活力、氧化应激、细胞周期和衰老相关指标。通过 western blot 检测 MAPK p38 和 ERK1/2 信号通路的蛋白表达水平。
结果
我们观察到 LEv、Exos 和 SF 均显示出改善 MPTP 诱导的 PD 模型小鼠运动功能障碍的潜力，其中 UCB-Exos 效果最为显著。UCB-Exos 在预防和治疗 PD 小鼠的运动功能障碍、认知下降和黑质病理损伤方面具有相当的疗效。进一步的研究表明，UCB-Exos 可能减轻神经元中的氧化损伤、衰老和退化以及能量代谢障碍。转录组测序结果证实，由于 UCB-Exos 差异表达的基因主要富集在神经活性配体-受体相互作用、多巴胺能突触和 MAPK 信号通路中。我们还观察到，UCB-Exos 显著抑制了 MAPK p38 和 ERK1/2 信号通路的过度磷酸化，无论是在体外还是体内。
结论
我们的研究对 UCB-Exos 的神经保护作用进行了全面评估，并表明通过调节 HspB1 和 Ppef2 的转录水平抑制 MAPK p38 和 ERK1/2 信号通路的过度磷酸化可能是 UCB-Exos 改善 PD 相关病理特征的关键机制。
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