Lu Mei-Hong, Ji Wen-Li, Chen Hong, Sun Yan-Yun, Zhao Xiu-Yun, Wang Fen, Shi Yi, Hu Yan-Ning, Liu Bo-Xiang, Wu Jing-Wen, Xu De-En, Zheng Jia-Wei, Liu Chun-Feng, Ma Quan-Hong
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.
School of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Front Aging Neurosci. 2021 Mar 10;13:650103. doi: 10.3389/fnagi.2021.650103. eCollection 2021.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates β-amyloid accumulation by upregulating the expression of β-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.
阿尔茨海默病（AD）是一种以记忆障碍为特征的神经退行性疾病，目前尚无有效治疗方法。干细胞移植在多种疾病的治疗中显示出巨大潜力。然而，由于存在血脑屏障，干细胞疗法在神经系统疾病，尤其是像AD这种病程较长的疾病中的应用受到递送方式的限制。到目前为止，在临床前和临床研究中，干细胞治疗神经系统疾病最常用的递送方式是颅内注射和鞘内注射，这两种方式都具有侵入性。在本研究中，我们通过向APP/PS1转基因小鼠脑内重复鼻内递送人类神经干细胞（hNSCs），来研究hNSCs对AD病理学的影响。结果表明，经鼻内移植的hNSCs能够存活，并表现出广泛迁移以及较高的神经元分化能力，而胶质细胞分化相对有限。一部分经鼻内移植的hNSCs分化为胆碱能神经元，可挽救APP/PS1小鼠的胆碱能功能障碍。此外，hNSCs的鼻内移植通过上调β-淀粉样蛋白降解酶、胰岛素降解酶和中性内肽酶的表达来减轻β-淀粉样蛋白的积累。而且，hNSCs的鼻内移植改善了包括神经炎症、胆碱能功能障碍、周细胞和突触丢失等其他类AD病理学特征，同时增强了成年海马神经发生，最终挽救了APP/PS1转基因小鼠的认知缺陷。因此，我们的研究结果突出表明，hNSCs的鼻内移植通过多种机制改善认知，并展现出鼻内给药干细胞作为AD非侵入性治疗策略的巨大潜力。
