Le Belle Janel E, Svendsen Clive N
Cambridge Centre for Brain Repair, Forvie Site, University of Cambridge, Cambridge, UK.
BioDrugs. 2002;16(6):389-401. doi: 10.2165/00063030-200216060-00001.
The use of stem cells in cell replacement therapy for neurodegenerative diseases has received a great deal of scientific and public interest in recent years. This is due to the remarkable pace at which paradigm-changing discoveries have been made regarding the neurogenic potential of embryonic, fetal, and adult cells. Over the last decade, clinical fetal tissue transplants have demonstrated that dopaminergic neurons can survive long term and provide functional clinical benefits for patients with Parkinson's disease. Pluripotent embryonic stem cells and multipotent neural stem cells may provide renewable sources that could replace these primary fetal grafts. Considerable advancement has been made in generating cultures with high numbers of neurons in general and of dopaminergic neurons using a varied array of techniques. However, much of this encouraging progress still remains to be tested on long-term expanded human cultures. Further problems include the low survival rate of these cells following transplantation and the tumorigenic tendencies of embryo-derived cells. However, pre-differentiation or genetic modification of stem cell cultures prior to transplantation may help lead to the generation of high numbers of cells of the desired phenotype following grafting. Boosting particular factors or substrates in the culture media may also protect grafted neurons from oxidative and metabolic stress, and provide epigenetic trophic support. Possible endogenous sources of cells for brain repair include the transdifferentiation of various types of adult cells into neurons. Despite the excitement generated by examples of this phenomenon, further work is needed in order to identify the precise instructive cues that generate neural cells from many other tissue types, and whether or not the new cells are functionally normal. Furthermore, issues such as cell homogeneity and fusion need to be addressed further before the true potential of transdifferentiation can be known. Endogenous stem cells also reside in the neurogenic zones of the adult brain (ventricle lining and hippocampus). Further elucidation of the mechanisms that stimulate cell division and migration are required in order to learn how to amplify the small amount of new cells generated by the adult brain and to direct these cells to areas of injury or degeneration. Finally, a more fundamental understanding of brain injury and disease is required in order to circumvent local brain environmental restrictions on endogenous cell differentiation and survival.
近年来，干细胞在神经退行性疾病的细胞替代疗法中的应用引起了科学界和公众的广泛关注。这是因为在胚胎、胎儿和成年细胞的神经发生潜能方面取得了显著的、改变范式的发现。在过去十年中，临床胎儿组织移植表明多巴胺能神经元可以长期存活，并为帕金森病患者提供功能性的临床益处。多能胚胎干细胞和多能神经干细胞可能提供可再生资源，以替代这些原始胎儿移植物。使用各种技术在培养大量神经元尤其是多巴胺能神经元方面已经取得了相当大的进展。然而，这一令人鼓舞的进展在很大程度上仍有待在长期扩增的人类培养物上进行测试。进一步的问题包括这些细胞在移植后的低存活率以及胚胎来源细胞的致瘤倾向。然而，移植前对干细胞培养物进行预分化或基因修饰可能有助于在移植后产生大量所需表型的细胞。在培养基中增加特定因子或底物也可能保护移植的神经元免受氧化和代谢应激，并提供表观遗传营养支持。脑修复的内源性细胞来源可能包括将各种类型的成年细胞转分化为神经元。尽管这种现象的例子引发了人们的兴奋，但仍需要进一步开展工作，以确定从许多其他组织类型产生神经细胞的确切诱导线索，以及新细胞在功能上是否正常。此外，在了解转分化的真正潜力之前，还需要进一步解决细胞同质性和融合等问题。内源性干细胞也存在于成人大脑的神经发生区（脑室衬里和海马体）。为了了解如何扩增成人大脑产生的少量新细胞并将这些细胞引导至损伤或退化区域，需要进一步阐明刺激细胞分裂和迁移的机制。最后，为了规避局部脑环境对内源性细胞分化和存活的限制，需要对脑损伤和疾病有更基本的了解。
