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在治疗神经退行性疾病的重编程干细胞衍生的前体细胞中的化学遗传调节

Deqiang Han¹, Xueyao Wang², Na Pan³

¹Cell Therapy Center, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University; National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education; handq@xwhosp.org.

Journal of visualized experiments : JoVE

|May 19, 2025

概括

仅由设计药物激活的设计受体 (DREADD) 能够在帕金森病中实现精确的神经元调制.

科学领域:

神经科学是一个神经科学.
干细胞生物学干细胞生物学
药理学药理学是指药理学的学科.

背景情况:

帕金森病 (PD) 是一种神经退行性疾病,其特征是多巴胺能神经元的损失.
基于干细胞的疗法提供了神经元替代和功能恢复的潜力.
精确控制移植细胞活动对于治疗疗效至关重要.

研究的目的:

在帕金森病小鼠模型中评估表达DREADD受体的CRISPR工程干细胞的功能整合和调制.
评估激活刺激性 (hM3Dq) 和抑制性 (hM4Di) DREADD受体对移植的多巴胺基前体的影响.
验证DREADD技术在干细胞治疗中用于精确的神经元调制的使用.

主要方法:

用CRISPR工程的人类重新编程干细胞的生成,表达非融合hM3Dq或hM4Di DREADD受体.
干细胞分化为中脑多巴胺基前体,并移植到6-OHDA受损小鼠的条形体中.
行为评估 (例如,气测试) 和电生理记录 (例如,SEPSC分析) 来评估细胞功能和主机电路集成.

主要成果:

移植的细胞在施用克洛扎-N-氧化物 (CNO) 后以DREADD依赖的方式调节了运动功能.
激活hM4Di会减少对侧前肢运动,而激活hM3Dq会增强运动行为.
电生理学记录证实了DREADD介导的突触调制,hM4Di减少,hM3Dq增加刺激信号.

结论:

在帕金森病模型中,表达DREADD受体的CRISPR工程干细胞可以精确调节.
这种方法可以对移植细胞活动进行有针对性的控制,从而影响宿主神经电路的功能.
将DREADD技术与干细胞疗法的整合为先进的神经治疗提供了前景.

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