Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Kyonggi-do, Korea.
Cells. 2022 Mar 18;11(6):1029. doi: 10.3390/cells11061029.
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer's disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-β peptide (Aβ) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aβ induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aβ exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aβ. Silencing OPN via siRNA suppressed Aβ-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD.
本研究旨在验证人脑类器官（hBO）在阿尔茨海默病（AD）模型中用于研究人神经嵴来源的鼻甲骨干细胞（hNTSCs）的治疗潜力和机制。我们从人诱导多能干细胞中生成 hBO，根据神经元标志物和电生理特征研究其特征，然后评估 hNTSCs 在体外 hBO 中和体内 AD 小鼠模型中对淀粉样β肽（Aβ）神经毒性活性的保护作用。用 Aβ 处理 hBO 会诱导神经元细胞死亡，同时伴随神经元标志物表达减少，而在 Aβ 暴露下与 hNTSCs 共培养则抑制了这种减少。细胞因子阵列显示，与仅存在 Aβ的 hBO 相比，与 hNTSCs 共培养的 hBO 中骨桥蛋白（OPN）水平显著降低。通过 siRNA 沉默 OPN 可抑制细胞培养中 Aβ诱导的神经元细胞死亡。值得注意的是，与 PBS 相比，hNTSC 移植后 AD 小鼠模型的水迷宫测试表现明显改善，移植后 OPN 水平降低。这些发现表明 hBO 模型可用于评估干细胞的治疗效果和机制，以应用于 AD 的治疗。
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