Wang Herui, Zhong Chonglin, Mi Yi, Li Guo, Zhang Chenliang, Chen Yaoyao, Li Xin, Liu Yongjun, Liu Guangyang
Stem Cell Biology and Regenerative Medicine Department, Yi-Chuang Institute of Bio-Industry, Beijing 100176, China.
Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Bioengineering (Basel). 2025 Jun 12;12(6):646. doi: 10.3390/bioengineering12060646.
Current therapies for Alzheimer's disease (AD) includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aβ)/Tau-targeting drugs. While these drugs improve cognitive decline and target the pathological mechanisms, their outcomes still are still in debate. Mesenchymal stem cells (MSCs) offer a regenerative approach by modulating neuroinflammation and promoting neuroprotection. Although the paracrine of MSCs is efficient in various AD preclinical studies and the exosomes of MSCs have entered clinical trials, the key cytokines driving the efficacy remain unclear. Here, we evaluated human umbilical cord-derived MSCs (hUC-MSCs) and employed gene-silenced MSCs (siHGF-MSCs, siTNFR1-MSCs, siBDNF-MSCs) in APP/PS1 AD mice to investigate specific mechanisms. hUC-MSCs significantly reduced Aβ/Tau pathology and neuroinflammation, with cytokine-specific contributions: silencing HGF predominantly reduced Aβ/Tau clearance, although silencing TNFR1 or BDNF showed modest effects; silencing TNFR1 or BDNF more prominently weakened anti-neuroinflammation, while silencing HGF exerted a weaker influence. All three cytokines partially contributed to oxidative stress reduction and cognitive improvements. Our study highlights MSC-driven AD alleviation as a multifactorial strategy and reveals specific cytokines alleviating different aspects of AD pathology.
目前治疗阿尔茨海默病（AD）的方法包括乙酰胆碱酯酶抑制剂、N-甲基-D-天冬氨酸（NMDA）受体拮抗剂以及靶向淀粉样β蛋白（Aβ）/tau蛋白的药物。虽然这些药物可改善认知功能衰退并针对病理机制，但它们的治疗效果仍存在争议。间充质干细胞（MSCs）通过调节神经炎症和促进神经保护提供了一种再生方法。尽管在各种AD临床前研究中MSCs的旁分泌作用有效，且MSCs的外泌体已进入临床试验，但驱动疗效的关键细胞因子仍不清楚。在此，我们评估了人脐带间充质干细胞（hUC-MSCs），并在APP/PS1 AD小鼠中使用基因沉默的MSCs（siHGF-MSCs、siTNFR1-MSCs、siBDNF-MSCs）来研究具体机制。hUC-MSCs显著减少了Aβ/tau病理和神经炎症，且细胞因子有特定作用：沉默肝细胞生长因子（HGF）主要降低Aβ/tau清除率，而沉默肿瘤坏死因子受体1（TNFR1）或脑源性神经营养因子（BDNF）的作用较小；沉默TNFR1或BDNF更显著地削弱了抗神经炎症作用，而沉默HGF的影响较弱。所有这三种细胞因子都在一定程度上有助于减轻氧化应激和改善认知功能。我们的研究强调了MSCs驱动的AD缓解是一种多因素策略，并揭示了特定细胞因子可缓解AD病理的不同方面。
