人鼻腔下鼻甲衍生神经干细胞通过调节 Hippo 信号改善帕金森病模型中黑质致密部的微环境。
Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson's Disease Model by Modulating Hippo Signaling.
机构信息
Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
Postech-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
出版信息
Tissue Eng Regen Med. 2024 Jul;21(5):737-748. doi: 10.1007/s13770-024-00635-3. Epub 2024 Apr 10.
BACKGROUND
Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases, following Alzheimer's disease. The onset of PD is characterized by the loss of dopaminergic neurons in the substantia nigra. Stem cell therapy has great potential for the treatment of neurodegenerative diseases, and human nasal turbinate-derived stem cells (hNTSCs) have been found to share some characteristics with mesenchymal stem cells. Although the Hippo signaling pathway was originally thought to regulate cell size in organs, recent studies have shown that it can also control inflammation in neural cells.
METHODS
Dopaminergic neuron-like cells were differentiated from SH-SY5Y cells (DA-Like cells) and treated with 1-Methyl-4-phenylpyridinium iodide to stimulate Reactive oxidative species (ROS) production. A transwell assay was conducted to validate the effect of hNTSCs on the Hippo pathway. We generated an MPTP-induced PD mouse model and transplanted hNTSCs into the substantia nigra of PD mice via stereotaxic surgery. After five weeks of behavioral testing, the brain samples were validated by immunoblotting and immunostaining to confirm the niche control of hNTSCs.
RESULTS
In-vitro experiments showed that hNTSCs significantly increased cell survival and exerted anti-inflammatory effects by controlling ROS-mediated ER stress and hippocampal signaling pathway factors. Similarly, the in-vivo experiments demonstrated an increase in anti-inflammatory effects and cell survival rate. After transplantation of hNTSCs, the PD mouse model showed improved mobility and relief from PD symptoms.
CONCLUSION
hNTSCs improved the survival rate of dopaminergic neurons by manipulating the hippocampal pathway through Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) by reducing inflammatory cytokines. In this study, we found that controlling the niche of hNTSCs had a therapeutic effect on PD lesions.
背景
帕金森病（PD）是仅次于阿尔茨海默病的最常见的神经退行性疾病之一。PD 的发病特征是黑质多巴胺能神经元的丧失。干细胞治疗在治疗神经退行性疾病方面具有巨大的潜力，并且已经发现人鼻甲骨源性干细胞（hNTSC）与间充质干细胞具有一些共同特征。虽然 Hippo 信号通路最初被认为是调节器官细胞大小的，但最近的研究表明，它还可以控制神经细胞的炎症。
方法
将 SH-SY5Y 细胞（DA 样细胞）分化为多巴胺能神经元样细胞，并使用 1-甲基-4-苯基吡啶碘化物（1-Methyl-4-phenylpyridinium iodide，MPP+）刺激活性氧（reactive oxidative species，ROS）的产生。通过 Transwell 测定法验证 hNTSC 对 Hippo 通路的影响。我们构建了一个 MPTP 诱导的 PD 小鼠模型，并通过立体定向手术将 hNTSC 移植到 PD 小鼠的黑质中。在五周的行为测试后，通过免疫印迹和免疫组织化学验证大脑样本，以确认 hNTSC 的龛位控制作用。
结果
体外实验表明，hNTSC 通过控制 ROS 介导的内质网应激和 Hippo 信号通路因子，显著提高细胞存活率并发挥抗炎作用。同样，体内实验也表明抗炎作用和细胞存活率增加。移植 hNTSC 后，PD 小鼠模型的运动能力得到改善，PD 症状得到缓解。
结论
hNTSC 通过减少炎症细胞因子，通过 Yes 相关蛋白（Yes-associated protein，YAP）/含 PDZ 结合模体的转录共激活因子（transcriptional coactivator with a PDZ-binding motif，TAZ）调控 Hippo 通路，提高多巴胺能神经元的存活率。在这项研究中，我们发现控制 hNTSC 的龛位对 PD 病变具有治疗作用。
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