Regenerative Medicine for the Aging Brain.
Regenerative Medicine for the Aging Brain.
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DOI：
10.18650/2379-5751.11001
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
M. López-León;P. Reggiani;C. Hereñú;R. Goya
中科院分区：
文献类型：
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作者：
M. López-León;P. Reggiani;C. Hereñú;R. Goya
在中枢神经系统中，胆碱能和多巴胺能 (DA) 神经元是最容易受到年龄有害影响的细胞之一。因此，已知基底前脑胆碱能系统在正常衰老过程中会经历中度的神经退行性变化，而在阿尔茨海默病（AD）中会经历严重的萎缩。帕金森病 (PD) 是黑质纹状体 DA 神经元的变性，是 DA 神经元对年龄的脆弱性的最明显反映。在这种情况下，细胞重编程为治疗这些破坏性疾病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，成年哺乳动物细胞可以通过一些胚胎转录因子（TF）的过度表达而重新编程为多能状态。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。尽管可以将 iPSC 重新分化为特定的体细胞类型，但未能分化的污染 iPSC 的致瘤潜力增加了该过程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 microRNA 的转基因表达将一种成体细胞类型直接转化为另一种成体细胞类型。另一种方法称为直接重编程，具有多种优点，例如使用通用转录因子系统以及产生再生的多能祖细胞群的能力，能够响应特定的分化因子分化成特定的细胞类型。这些新方法为治疗与特定细胞类型丧失相关的病理学提供了新的希望，例如黑质 DA 神经元（PD 中）或 AD 早期阶段的基底前脑胆碱能神经元。此处回顾了上述主题。
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.