Lear Bo P, Moore Darcie L
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, United States.
Front Neurosci. 2023 Jun 22;17:1198041. doi: 10.3389/fnins.2023.1198041. eCollection 2023.
Axon regeneration is limited in the adult mammalian central nervous system (CNS) due to both intrinsic and extrinsic factors. Rodent studies have shown that developmental age can drive differences in intrinsic axon growth ability, such that embryonic rodent CNS neurons extend long axons while postnatal and adult CNS neurons do not. In recent decades, scientists have identified several intrinsic developmental regulators in rodents that modulate growth. However, whether this developmentally programmed decline in CNS axon growth is conserved in humans is not yet known. Until recently, there have been limited human neuronal model systems, and even fewer age-specific human models. Human models range from pluripotent stem cell-derived neurons to directly reprogrammed (transdifferentiated) neurons derived from human somatic cells. In this review, we discuss the advantages and disadvantages of each system, and how studying axon growth in human neurons can provide species-specific knowledge in the field of CNS axon regeneration with the goal of bridging basic science studies to clinical trials. Additionally, with the increased availability and quality of 'omics datasets of human cortical tissue across development and lifespan, scientists can mine these datasets for developmentally regulated pathways and genes. As there has been little research performed in human neurons to study modulators of axon growth, here we provide a summary of approaches to begin to shift the field of CNS axon growth and regeneration into human model systems to uncover novel drivers of axon growth.
由于内在和外在因素,轴突再生在成年哺乳动物中枢神经系统(CNS)中受到限制。啮齿动物研究表明,发育年龄可导致内在轴突生长能力的差异,例如胚胎期啮齿动物中枢神经系统神经元能长出长轴突,而出生后及成年中枢神经系统神经元则不能。近几十年来,科学家们在啮齿动物中鉴定出了几种调节生长的内在发育调节因子。然而,这种中枢神经系统轴突生长中由发育程序决定的衰退在人类中是否保守尚不清楚。直到最近,人类神经元模型系统一直有限,特定年龄的人类模型更少。人类模型从多能干细胞衍生的神经元到直接重编程(转分化)的源自人类体细胞的神经元。在这篇综述中,我们讨论了每个系统的优缺点,以及研究人类神经元中的轴突生长如何能够在中枢神经系统轴突再生领域提供物种特异性知识,目标是将基础科学研究与临床试验联系起来。此外,随着整个发育和生命周期中人类皮质组织“组学”数据集的可用性和质量不断提高,科学家们可以挖掘这些数据集以寻找发育调节的途径和基因。由于在人类神经元中进行的研究很少,难以研究轴突生长的调节因子,因此我们在此总结了一些方法,以开始将中枢神经系统轴突生长和再生领域转向人类模型系统,以发现轴突生长的新驱动因素。