Direct neuronal reprogramming converts somatic cells of a defined lineage into induced neuronal cells without going through a pluripotent intermediate. This approach not only provides access to the otherwise largely inaccessible cells of the brain for neuronal disease modeling, but also holds great promise for ultimately enabling neuronal cell replacement without the use of transplantation. To improve efficiency and specificity of direct neuronal reprogramming, much of the current efforts aim to understand the mechanisms that safeguard cell identities and how the reprogramming cells overcome the barriers resisting fate changes. Here, we review recent discoveries into the mechanisms by which the donor cell program is silenced, and new cell identities are established. We also discuss advancements that have been made toward fine-tuning the output of these reprogramming systems to generate specific types of neuronal cells. Finally, we highlight the benefit of using direct neuronal reprogramming to study age-related disorders and the potential of in vivo direct reprogramming in regenerative medicine.

直接神经元重编程将特定谱系的体细胞转化为诱导神经元细胞，而无需经过多能中间体。这种方法不仅为神经元疾病建模提供了访问基本上无法访问的大脑细胞的途径，而且还为最终实现不使用移植的神经元细胞替代提供了巨大的希望。为了提高直接神经元重编程的效率和特异性，当前的大部分努力旨在了解保护细胞身份的机制以及重编程细胞如何克服抵抗命运改变的障碍。在这里，我们回顾了最近对供体细胞程序沉默和建立新细胞身份的机制的发现。我们还讨论了在微调这些重编程系统的输出以生成特定类型的神经元细胞方面所取得的进展。最后，我们强调了使用直接神经元重编程来研究与年龄相关的疾病的好处以及体内直接重编程在再生医学中的潜力。