Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease.
Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease.
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DOI：
10.1016/j.stem.2016.03.014
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发表时间：
2016-06-02
期刊：
影响因子：
23.9
通讯作者：
Zhang SC
中科院分区：
文献类型：
--
作者：
Chen Y;Xiong M;Dong Y;Haberman A;Cao J;Liu H;Zhou W;Zhang SC
移植人多能干细胞（hPSC）衍生的神经元是治疗包括帕金森病（PD）在内的疾病的一种有前途的途径。非常需要对移植细胞活性的精确控制，因为细胞并不总是正确地整合到宿主电路中，并且可能导致次优的移植功能或不期望的结果。在这里，我们在PD小鼠模型中展示了移植从经工程改造以表达DREADD（仅由设计药物激活的设计受体）的hPSC分化的人中脑多巴胺（mDA）神经元后，对运动功能的可调拯救。管理氯氮平-N-氧化物（CNO）能够精确DREADD依赖性刺激或抑制移植神经元，揭示D1受体依赖性调节宿主神经元电路的移植细胞。移植的细胞挽救了运动缺陷，这可以通过基于hoc的移植功能控制来逆转或增强，并且激活移植的细胞驱动移植小鼠的行为变化。这些结果突出了细胞移植后外源性和非侵入性控制和改善治疗结果的能力。
Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson’s disease (PD). Precise control over engrafted cell activity is highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.