X-linked severe combined immunodeficiency (X-SCID) rats for xeno-transplantation and behavioral evaluation
X-linked severe combined immunodeficiency (X-SCID) rats for xeno-transplantation and behavioral evaluation
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DOI：
10.1016/j.jneumeth.2015.01.027
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发表时间：
2015-03-30
影响因子：
3
通讯作者：
Takahashi, Jun
中科院分区：
文献类型：
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作者：
Samata, Bumpei;Kikuchi, Tetsuhiro;Takahashi, Jun
背景：为了评价人多巴胺能（DA）神经元的体内功能，半外侧注射6-羟基多巴胺（6-OHDA）构建帕金森病（PD）模型大鼠被广泛用作宿主动物。然而，在这种异种移植的情况下，为了移植细胞的良好存活，需要免疫抑制。新方法：为了确定人类成熟神经元能否在没有免疫抑制的情况下在x -连锁严重联合免疫缺陷（X-SCID）大鼠体内存活，我们将人胚胎干细胞（ESC）来源的DA神经元移植到x -连锁严重联合免疫缺陷（X-SCID）大鼠纹状体中。接下来，我们用6-OHDA和移植的小鼠胎儿DA神经元或人诱导多能干细胞（iPSC）来源的DA神经元处理X-SCID大鼠，以观察这些大鼠是否可以作为PD模型大鼠。结果：X-SCID大鼠对人esc来源的DA神经元没有引起免疫应答，因此细胞存活良好，没有免疫抑制。此外，6- ohda损伤的X-SCID大鼠表现出旋转行为，通过移植小鼠胎儿DA神经元或人ipsc来源的DA神经元可以恢复。与现有方法的比较：环孢素A等药物的免疫抑制需要每天注射，这对大鼠有压力，而且可能导致肾功能或肝功能衰竭。此外，药物的血液水平可能不稳定，这削弱了数据的可靠性。结论：我们的研究结果为评估人类DA神经元的体内功能提供了一种更容易获得和可靠的方法，可能为多能干细胞的应用提供临床前研究。(C) 2015 Elsevier B.V.版权所有
Background: To evaluate the in vivo function of human dopaminergic (DA) neurons, Parkinson's disease (PD) model rats made by the hemi-lateral injection of 6-hydroxydopamine (6-OHDA) are widely used as host animals. In the case of such xeno-transplantation, however, immunosuppression is needed for good survival of the grafted cells.New methods: In order to determine whether human mature neurons can survive in X-linked severe combined immunodeficiency (X-SCID) rats without immunosuppression, we grafted human embryonic stem cell (ESC)-derived DA neurons into the striatum of X-SCID rats. We next treated the X-SCID rats with 6-OHDA and grafted mouse fetal DA neurons or human induced pluripotent stem cell (iPSC)-derived DA neurons to examine whether these rats can be used as PD model rats.Results: X-SCID rats did not elicit immune responses against human ESC-derived DA neurons and consequently resulted in good survival of the cells without immunosuppression. Furthermore, 6-OHDA-lesioned X-SCID rats exhibited rotational behavior, which was recovered by grafting mouse fetal DA neurons or human iPSC-derived DA neurons.Comparison with existing methods: Immunosuppression by drugs such as Cyclosporine A requires daily injection, which is stressful for rats and moreover may cause renal or hepatic failure. Furthermore, blood levels of the drug may not be stable, which weakens the reliability of the data.Conclusions: Our results provide a more accessible and reliable method to evaluate the in vivo function of human DA neurons, potentially offering a pre-clinical study for the application of pluripotent stem cells. (C) 2015 Elsevier B.V. All rights reserved.