A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells
A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells
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DOI：
10.1016/j.stem.2022.01.013
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发表时间：
2022-03-03
期刊：
影响因子：
23.9
通讯作者：
Thompson, Lachlan H.
中科院分区：
文献类型：
--
作者：
Moriarty, Niamh;Gantner, Carlos W.;Thompson, Lachlan H.
中脑多巴胺（mDA）神经元可以在帕金森病（PD）患者中被替换，以提供运动功能的长期改善。成人大脑中长距离轴突生长的能力有限，这意味着细胞被异位移植到纹状体靶区。因此，几种mDA途径没有恢复，这可能是患者运动功能恢复不完全的基础。在这里，我们表明，GDNF的病毒传递到纹状体，结合人类多能干细胞衍生的mDA神经元的同源移植，概括了全脑mDA靶神经支配。移植物提供了纹状体多巴胺水平的恢复和运动功能的校正，以及与异位移植物没有很好神经支配的其他mDA靶核的连接。这些结果表明，通过将适当的生长因子信号传导与特定细胞类型的移植相匹配，在成年人大脑中实现长距离电路的功能和解剖学上精确重建的显著能力。
Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.