亨廷顿氏病(HD)是一种常染色体显性遗传性疾病,尤其导致纹状体中DARPP-32阳性中刺投射神经元(“MSN”)的丧失。尚无已知的HD治愈方法,但疾病早期细胞丢失的相对特异性使通过神经移植进行细胞置换成为有吸引力的治疗可能性。人胎儿纹状体前体细胞的移植在临床试验中显示出“原理证明”;然而,与来源胎儿组织相关的实践和伦理困难刺激了确定更容易获得且更适合标准化的供体细胞替代来源的需要.我们现在已经获得了从多能干细胞产生DARPP-32阳性MSN样神经元的第一代方案,这些方案已经成功地移植到HD的动物模型中。然而,这些移植是否能提供稳定的功能恢复,达到胎儿纹状体移植的正常水平还有待证实.特别令人关注的是,原代胎儿纹状体移植物不是同质的;它们不仅包含纹状体投射神经元的MSN亚群,而且还包括构成成熟纹状体的所有不同细胞类型,例如纹状体中间神经元和纹状体神经胶质的多个群体,这肯定有助于正常的纹状体功能。相比之下,目前多能干细胞分化的方案几乎完全针对仅指定MSN谱系的神经元。到目前为止,干细胞来源的移植物的功能和整合的证据相应地有限.的确,考虑到使用原发性胎儿纹状体移植物实现的完整纹状体重建的特征,表明在HD中下一代干细胞来源的替代疗法的最佳成功将需要开发移植方案以允许包含多种纹状体细胞类型。例如中间神经元和/或神经胶质。几乎可以肯定,因此,更复杂的区分协议将是必要的,超越特定群体的MSN替换。对这一技术挑战的合理解决方案要求我们重新解决潜在的问题-什么构成了功能性纹状体移植物?
Huntington\'s disease (HD) is an autosomal dominant inherited disorder leading to the loss inter alia of DARPP-32 positive medium spiny projection neurons (\"MSNs\") in the striatum. There is no known cure for HD but the relative specificity of cell loss early in the disease has made cell replacement by neural transplantation an attractive therapeutic possibility. Transplantation of human fetal striatal precursor cells has shown \"proof-of-principle\" in clinical trials; however, the practical and ethical difficulties associated with sourcing fetal tissues have stimulated the need to identify alternative source(s) of donor cells that are more readily available and more suitable for standardization. We now have available the first generation of protocols to generate DARPP-32 positive MSN-like neurons from pluripotent stem cells and these have been successfully grafted into animal models of HD. However, whether these grafts can provide stable functional recovery to the level that can regularly be achieved with primary fetal striatal grafts remains to be demonstrated. Of particular concern, primary fetal striatal grafts are not homogenous; they contain not only the MSN subpopulation of striatal projection neurons but also include all the different cell types that make up the mature striatum, such as the multiple populations of striatal interneurons and striatal glia, and which certainly contribute to normal striatal function. By contrast, present protocols for pluripotent stem cell differentiation are almost entirely targeted at specifying just neurons of an MSN lineage. So far, evidence for the functionality and integration of stem-cell derived grafts is correspondingly limited. Indeed, consideration of the features of full striatal reconstruction that is achieved with primary fetal striatal grafts suggests that optimal success of the next generations of stem cell-derived replacement therapy in HD will require that graft protocols be developed to allow inclusion of multiple striatal cell types, such as interneurons and/or glia. Almost certainly, therefore, more sophisticated differentiation protocols will be necessary, over and above replacement of a specific population of MSNs. A rational solution to this technical challenge requires that we re-address the underlying question-what constitutes a functional striatal graft?