Laboratory of Neurobiology, Príncipe Felipe Research Centre, Valencia, 46012, Spain.
Optical and Confocal Microscopy Service, Príncipe Felipe Research Centre, Valencia, 46012, Spain.
J Neuroimmune Pharmacol. 2024 Oct 9;19(1):52. doi: 10.1007/s11481-024-10153-7.
Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.
肝硬化患者可能表现出轻微的肝性脑病（MHE），伴有轻度认知障碍和运动缺陷。血氨升高和炎症是导致 MHE 认知和运动改变的主要原因。高氨血症大鼠可复制这些改变。目前尚无针对 MHE 神经改变的特异性治疗方法。间充质干细胞（MSC）衍生的细胞外囊泡（MSC-EVs）在治疗炎症和免疫性疾病方面具有广阔的应用前景。我们旨在评估 MSC-EVs 是否能减轻高氨血症大鼠小脑的神经炎症，恢复运动协调，并研究相关机制。我们通过静脉注射 MSC-EVs 研究了 MSC-EVs 的体内作用，并在小脑切片上进行了体外研究。采用平衡木行走试验分析运动协调情况。通过免疫组化、免疫荧光和 Western blot 评估神经炎症的影响。MSC-EVs 的注射可减少小脑内小胶质细胞和星形胶质细胞的激活，并恢复高氨血症大鼠的运动协调。体外实验表明，MSC-EVs 可使 TNFα 等促炎因子、NF-kB 激活以及导致运动不协调的两条关键途径（TNFR1-NF-kB-谷氨酰胺酶-GAT3 和 TNFR1-CCL2-BDNF-TrkB-KCC2）的活性恢复正常。EVs 中的 TGFβ 对于这些有益作用是必需的。MSC-EVs 治疗可逆转高氨血症大鼠小脑的神经炎症及其导致运动不协调的潜在机制。MSC-EVs 治疗可能有助于改善 MHE 患者的运动功能。
