Abstract：
Transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) is considered to be a promising therapy for spinal cord injury (SCI) and will soon be translated to the clinical phase. However, how grafted neuronal activity influences functional recovery has not been fully elucidated. Here, we show the locomotor functional changes caused by inhibiting the neuronal activity of grafted cells using a designer receptor exclusively activated by designer drugs (DREADD). In vitro analyses of inhibitory DREADD (hM4Di)-expressing cells demonstrated the precise inhibition of neuronal activity via administration of clozapine N-oxide. This inhibition led to a significant decrease in locomotor function in SCI mice with cell transplantation, which was exclusively observed following the maturation of grafted neurons. Furthermore, trans-synaptic tracing revealed the integration of graft neurons into the host motor circuitry. These results highlight the significance of engrafting functionally competent neurons by hiPSC-NS/PC transplantation for sufficient recovery from SCI.
摘要：
源自人诱导多能干细胞(hiPSC)的神经干/祖细胞(NS/PC)的移植被认为是脊髓损伤(SCI)的有希望的疗法,并且将很快转化为临床阶段。然而,移植神经元活动如何影响功能恢复尚未完全阐明。这里,我们显示了通过使用专门由设计药物（DREADD）激活的设计受体抑制移植细胞的神经元活性而引起的运动功能变化。抑制性DREADD（hM4Di）表达细胞的体外分析表明，通过施用氯氮平N-氧化物可以精确抑制神经元活性。这种抑制作用导致SCI小鼠细胞移植后的运动功能显着下降，这是移植神经元成熟后唯一观察到的。此外，跨突触追踪显示移植神经元整合到宿主运动电路中。这些结果突出了通过hiPSC-NS/PC移植移植功能性有能力的神经元对于从SCI充分恢复的重要性。
