Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.
Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons.
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DOI：
10.1002/stem.1415
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发表时间：
2013-08
期刊：
影响因子：
5.2
通讯作者：
Isacson, Ole
中科院分区：
文献类型：
--
作者：
Sundberg, Maria;Bogetofte, Helle;Lawson, Tristan;Jansson, Johan;Smith, Gaynor;Astradsson, Arnar;Moore, Michele;Osborn, Teresia;Cooper, Oliver;Spealman, Roger;Hallett, Penelope;Isacson, Ole
关键词：
帕金森病的主要运动症状是由于中脑腹侧（VM）多巴胺能（DA）神经元的丢失。对于未来用细胞移植治疗帕金森病，重要的是开发用于产生人iPSC和hESC衍生的中脑型DA神经元的有效分化方法。在这里，我们描述了一种有效的分化和分选策略DA-神经元从人ES/iPS细胞和非人灵长类iPSC。使用非人灵长类iPSC进行神经元分化和自体移植对于临床前评估干细胞衍生的DA神经元的安全性和功效是重要的。本研究的目的是提高人和非人灵长类动物-iPSC（PiPSC）衍生的DA神经元的安全性。根据我们的结果，NCAM+/CD 29低分选富集来自多能干细胞衍生的神经细胞群的VM DA-神经元。NCAM+/CD 29低DA-神经元对FOXA 2/TH和EN 1/TH呈阳性，并且与未分选的神经细胞群相比，该细胞群具有增加的FOXA 2、LMX 1A、TH、GIRK 2、PITX 3、EN 1、GIRK 1 mRNA表达水平。PiPSC衍生的NCAM+/CD 29 low DA-神经元能够在移植后16周恢复6-OHDA损伤大鼠的运动功能。移植的分选细胞也整合在啮齿动物脑组织中，具有宿主纹状体的强TH+/hNCAM+神经炎性神经支配。自体移植一年后，灵长类iPSC衍生的神经细胞在一只灵长类动物的纹状体中存活，没有任何免疫抑制。这些神经细胞移植物在移植部位含有FOXA 2/TH阳性神经元。这是未来iPSC衍生细胞移植疗法的可行性和安全性的重要概念证明。
The main motor symptoms of Parkinson’s disease are due to the loss of dopaminergic (DA) neurons in the ventral midbrain (VM). For the future treatment of Parkinson’s disease with cell transplantation it is important to develop efficient differentiation methods for production of human iPSCs and hESCs-derived midbrain-type DA neurons. Here we describe an efficient differentiation and sorting strategy for DA-neurons from both human ES/iPS cells and non-human primate iPSCs. The use of non-human primate iPSCs for neuronal differentiation and autologous transplantation is important for pre-clinical evaluation of safety and efficacy of stem cell-derived DA neurons. The aim of this study was to improve the safety of human- and non-human primate-iPSC (PiPSC)-derived DA neurons. According to our results, NCAM+/CD29low sorting enriched VM DA-neurons from pluripotent stem cell-derived neural cell populations. NCAM+/CD29low DA-neurons were positive for FOXA2/TH and EN1/TH and this cell population had increased expression levels of FOXA2, LMX1A, TH, GIRK2, PITX3, EN1, NURR1 mRNA compared to unsorted neural cell populations. PiPSC-derived NCAM+/CD29low DA-neurons were able to restore motor function of 6-OHDA lesioned rats 16 weeks after transplantation. The transplanted sorted cells also integrated in the rodent brain tissue, with robust TH+/hNCAM+ neuritic innervation of the host striatum. One year after autologous transplantation, the primate iPSC-derived neural cells survived in the striatum of one primate without any immunosuppression. These neural cell grafts contained FOXA2/TH-positive neurons in the graft site. This is an important proof of concept for the feasibility and safety of iPSC-derived cell transplantation therapies in the future.
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影响因子：
5.2
作者：
Deleidi, Michela;Hargus, Gunnar;Hallett, Penelope;Osborn, Teresia;Isacson, Ole
通讯作者：
Isacson, Ole
影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
14.5
作者：
Mendez, I;Sanchez-Pernaute, R;Isacson, O
通讯作者：
Isacson, O
影响因子：
23.9
作者：
Fasano CA;Chambers SM;Lee G;Tomishima MJ;Studer L
通讯作者：
Studer L
影响因子：
16.2
作者：
HYNES, M;PORTER, JA;ROSENTHAL, A
通讯作者：
ROSENTHAL, A