Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer's disease

IF 15.5 1区 医学 Q1 CELL BIOLOGY Journal of Extracellular Vesicles Pub Date : 2024-11-05 DOI:10.1002/jev2.12519
Leelavathi N. Madhu, Maheedhar Kodali, Raghavendra Upadhya, Shama Rao, Yogish Somayaji, Sahithi Attaluri, Bing Shuai, Maha Kirmani, Shreyan Gupta, Nathaniel Maness, Xiaolan Rao, James J. Cai, Ashok K. Shetty
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Abstract

As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice. IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocyte soma and processes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-inflammasome and interferon-1 (IFN-1) signalling displayed reduced expression in microglia. Adding hiPSC-NSC-EVs to cultured human microglia challenged with amyloid-beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen-activated protein kinase and IFN-1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function. Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.

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来自人类诱导多能干细胞衍生神经干细胞的细胞外囊泡能减轻阿尔茨海默病中与疾病相关的小胶质细胞内的促炎级联反应
由于目前治疗阿尔茨海默病(AD)的方法缺乏改变疾病的干预措施,因此能够抑制AD进展并维持更好大脑功能的新型疗法具有重要意义。从人类诱导多能干细胞(hiPSC)衍生的神经干细胞(NSCs)中提取的抗炎细胞外囊泡(EVs)有望成为治疗阿尔茨海默病的疾病调节生物制剂。本研究通过检测3个月大的5xFAD小鼠鼻内注射(IN)hiPSC-NSC-EVs的效果,直接解决了这一问题。通过鼻内注射 hiPSC-NSC-EVs 进入小胶质细胞(包括斑块相关的小胶质细胞),并与大脑中的星形胶质细胞体和过程相遇。单细胞 RNA 测序显示,转录组变化表明小胶质细胞和星形胶质细胞的活化程度降低。与疾病相关的小胶质细胞、NOD-、LRR-和含吡咯啉结构域蛋白3(NLRP3)-炎症体和干扰素-1(IFN-1)信号相关的多个基因在小胶质细胞中的表达量减少。向受到淀粉样β寡聚体挑战的人小胶质细胞培养物中添加 hiPSC-NSC-EVs 也会产生类似的效果。星形胶质细胞中与 IFN-1 和白细胞介素-6 信号相关的基因表达也有所减少。此外,hiPSC-NSC-EV对海马小胶质细胞的调节作用在EV处理后2个月仍持续存在,且不影响其吞噬功能。小胶质细胞集群和炎性体复合物的减少、介质浓度的降低、NLRP3炎性体活化终产物的减少、参与激活p38/介原激活蛋白激酶和IFN-1信号的基因和/或蛋白的表达以及吞噬功能的改变都证明了这种作用。海马中的星形胶质细胞肥大程度、淀粉样蛋白-β斑块和 p-tau 也有所减少。hiPSC-NSC-EV的这种调节作用还能改善认知和情绪功能。因此,通过减少不良的神经炎症信号级联、淀粉样蛋白-β斑块负荷和p-tau,对AD进行早期hiPSC-NSC-EV干预可维持更好的大脑功能。这些结果首次证明了hiPSC-NSC-EV通过诱导活化小胶质细胞和反应性星形胶质细胞的转录组变化,在AD模型中抑制神经炎症信号级联的功效。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
期刊最新文献
A switch from lysosomal degradation to secretory autophagy initiates osteogenic bone metastasis in prostate cancer Correction to MAP kinase kinase 1 (MEK1) within extracellular vesicles inhibits tumour growth by promoting anti-tumour immunity A novel multiplexed immunoassay for surface-exposed proteins in plasma extracellular vesicles Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer's disease Real-time monitoring of small extracellular vesicles (sEVs) by in vivo flow cytometry
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