中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (12): 1914-1916.doi: 10.4103/1673-5374.169621

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

多能干细胞至纹状体投射神经元:还差“激活素A”的距离

  

  • 收稿日期:2015-09-10 出版日期:2015-12-30 发布日期:2015-12-30

Deriving striatal projection neurons from human pluripotent stem cells with Activin A

Zoe Noakes, Marija Fjodorova, Meng Li*   

  1. Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, Cardiff, UK
  • Received:2015-09-10 Online:2015-12-30 Published:2015-12-30
  • Contact: Meng Li, Ph.D., LiM26@cardiff.ac.uk.
  • Supported by:

    This work was supported by funding from the UK Medical Research Council, EU Framework Programme 7 Neurostemcell and Repair-HD.Presentations: BNA2015 Festival of Neuroscience; INTR12 2013.

摘要:

文章研究的中型多棘神经元稳定方法,为体外研究人类中型多棘神经元的发育提供了一个有益平台。来自他们实验室的高比例中型多棘神经元给细胞替代治疗亨廷顿氏病领域带来了曙光。然而,单独移植的中型多棘神经元可能不足以给亨廷顿氏病动物模型或病人带来功能上的恢复。因为纹状体小清蛋白中间神经元也严重影响着亨廷顿氏病,并且人类胎儿组织的研究表明,与神经节隆起单独移植相比,神经节整体隆起组织移植会有更好的生存率,并且与中型多棘神经元的融合率更强。因此,联合移植人多能干细胞衍生神经节隆起和内侧神经节隆起祖细胞是应该考虑的细胞替代治疗的方向。最后,他们已经能够在每个胚胎和诱导多能干细胞测试上复制这一发现,这为研究来源于亨廷顿氏病患者多能干细胞中治疗中的中型多棘神经元提供了可靠的工具。

Abstract:

The striatum is the main input structure of the basal ganglia and is involved in voluntary motor control, habit learning and reward processing. Medium spiny neurons (MSNs) comprise 80 and 95% of striatal neurons in primates and rodents, respectively, while the remaining population is made up of GABAergic and cholinergic interneurons. Up to 90% of MSNs are specifically lost in Huntington’s disease (HD), which is an inherited neurodegenerative disorder caused by an extended CAG-repeat mutation in the Huntingtin (HTT) gene. Although the exact mechanism by which mutant Htt protein disrupts striatal cell homeostasis and leads to MSN loss remains largely unknown, several studies using induced pluripotent stem cells (iPSCs) derived from patients have proven that this could be a powerful platform for understanding HD. Furthermore, with no disease-modifying treatment currently available, cell replacement has long been recognised as a potential therapy for HD. Human foetal tissue from the ganglionic eminences, the developmental birthplace of striatal neurons, has been used as a proof-of-principle in both pre-clinical animal studies and clinical trials. However, foetal tissue is in limited supply, involves ethical concerns and therapeutic product derived from it is impossible to quality-control; all of which could be avoided by using human PSCs (hPSCs) as a source of tissue for transplantation. In order to exploit the full potential of hPSCs, a robust differentiation paradigm is required to obtain an enriched population of MSNs in vitro and in vivo following transplantation. This Perspective will be focused on a recent discovery of a novel approach to generate MSNs from hPSCs using Activin A.