Lopez-Leon Micaela, Reggiani Paula C, Herenu Claudia B, Goya Rodolfo G
Enliven J Stem Cell Res Regen Med. 2014;1(1):1-9.
In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). Parkinson's disease (PD), a degeneration of nigro-striatal DA neurons is the most conspicuous reflection of the vulnerability of DA neurons to age. In this context, cell reprogramming offers novel therapeutic possibilities for the treatment of these devastating diseases. In effect, the generation of induced pluripotent stem cells (iPSCs) from somatic cells demonstrated that adult mammalian cells can be reprogrammed to a pluripotent state by the overexpression of a few embryonic transcription factors (TF). This discovery fundamentally widened the research horizon in the fields of disease modeling and regenerative medicine. Although it is possible to re-differentiate iPSCs to specific somatic cell types, the tumorigenic potential of contaminating iPSCs that failed to differentiate, increases the risk for clinical application of somatic cells generated by this procedure. Therefore, reprogramming approaches that bypass the pluripotent stem cell state are being explored. A method called lineage reprogramming has been recently documented. It consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage-specific TF or microRNAs. Another approach, termed direct reprogramming, features several advantages such as the use of universal TF system and the ability to generate a rejuvenated multipotent progenitor cell population, able to differentiate into specific cell types in response to a specific differentiation factors. These novel approaches offer a new promise for the treatment of pathologies associated with the loss of specific cell types as for instance, nigral DA neurons (in PD) or basal forebrain cholinergic neurons in the early stages of AD. The above topics are reviewed here.
在中枢神经系统中，胆碱能神经元和多巴胺能（DA）神经元是最易受衰老有害影响的细胞类型。因此，已知基底前脑胆碱能系统在正常衰老过程中会发生中度神经退行性变化，在阿尔茨海默病（AD）中会出现严重萎缩。帕金森病（PD）是黑质 - 纹状体DA神经元的退化，是DA神经元对衰老易感性的最显著体现。在此背景下，细胞重编程为这些毁灭性疾病的治疗提供了新的治疗可能性。实际上，从体细胞产生诱导多能干细胞（iPSC）表明，通过过表达几种胚胎转录因子（TF），成年哺乳动物细胞可以被重编程为多能状态。这一发现从根本上拓宽了疾病建模和再生医学领域的研究视野。虽然有可能将iPSC重新分化为特定的体细胞类型，但未分化的污染性iPSC的致瘤潜力增加了通过该程序产生的体细胞临床应用的风险。因此，正在探索绕过多能干细胞状态的重编程方法。最近记录了一种称为谱系重编程的方法。它包括通过多种谱系特异性TF或微小RNA的转基因表达将一种成年细胞类型直接转化为另一种成年细胞类型。另一种方法称为直接重编程，具有几个优点，例如使用通用TF系统以及能够产生恢复活力的多能祖细胞群体，该群体能够响应特定分化因子分化为特定细胞类型。这些新方法为治疗与特定细胞类型丧失相关的疾病提供了新的希望，例如帕金森病中的黑质DA神经元或阿尔茨海默病早期的基底前脑胆碱能神经元。本文将对上述主题进行综述。
