El Wazan Layal, Urrutia-Cabrera Daniel, Wong Raymond Ching-Bong
Cellular Reprogramming Unit, Centre for Eye Research Australia, Melbourne 3004, Australia.
World J Stem Cells. 2019 Jul 26;11(7):431-444. doi: 10.4252/wjsc.v11.i7.431.
Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries. However, a key challenge is the cellular source for transplantation which is often limited by donor availability. Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes , which have the potential to be used for autologous transplantation, as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy. Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic, GABAergic, dopaminergic, sensory and retinal neurons. We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes, and summarize their use in promoting direct reprogramming into different neuronal subtypes. Furthermore, we will discuss up-and-coming technologies that advance the cell reprogramming field, including the use of computational prediction of reprogramming factors, opportunity of cellular reprogramming using small chemicals and microRNA, as well as the exciting potential for applying direct reprogramming as a novel approach to promote neuro-regeneration within the body. Finally, we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.
细胞疗法在替代因神经退行性疾病或损伤而丢失的神经元方面展现出巨大潜力。然而，一个关键挑战是移植的细胞来源，其往往受限于供体的可获得性。直接重编程为生成特定的神经元亚型提供了一条令人兴奋的途径，这些亚型有潜力用于自体移植，以及在实验室中生成患者特异性疾病模型以用于药物发现和基因治疗测试。在此，我们对促进特定神经元亚型直接重编程的转录因子进行详细综述，特别关注谷氨酸能、γ-氨基丁酸能、多巴胺能、感觉和视网膜神经元。我们将讨论主转录调节因子和神经元亚型特异性因子在发育中的作用，并总结它们在促进直接重编程为不同神经元亚型中的应用。此外，我们将讨论推动细胞重编程领域发展的新兴技术，包括重编程因子的计算预测、使用小分子化学物质和微小RNA进行细胞重编程的机会，以及将直接重编程作为促进体内神经再生的新方法的令人兴奋的潜力。最后，我们将强调直接重编程的临床潜力，并讨论临床转化需要克服的障碍。
