Zhou Wenxuan, Xia Shiyue, Wang Chenmeng, Yang Qingwu, Verkhratsky Alexei, Niu Jianqin
Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, China.
Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
Cell Death Dis. 2025 Jul 31;16(1):580. doi: 10.1038/s41419-025-07893-6.
Rodents are the most commonly used laboratory animals in medical research. However, significant evolutionary divergences between humans and rodents, particularly in the complexity of white matter connectome, which are fundamentally shaped by myelin as their major structural component, pose critical challenges in modeling the human neurological diseases. Given the divergences and central roles of myelin in pathology, a thorough reevaluation of the rodent models used in contemporary research is critical, alongside the careful selection, optimization, or de novo development of models that faithfully recapitulate human white matter disorders. In this review, we summarize the strengths and limitations of existing rodent models, emphasizing their contributions to understanding demyelinating pathologies across autoimmune, neurodegenerative, vascular, perinatal, traumatic, infectious and genetic diseases. We also overview white mater disease models using other species and human stem cells. Subsequently we discuss critical interspecies differences in white matter biology that may limit translational relevance, while highlighting how rodent models enhance our comprehension of various pathological conditions. Lastly, we outline strategies to refine rodent models through advanced genetic engineering, humanized microenvironments, and multimodal phenotyping, with the goal of progressively improving existing them to increase their preclinical translational potentials.
啮齿动物是医学研究中最常用的实验动物。然而，人类与啮齿动物之间存在显著的进化差异，尤其是在白质连接组的复杂性方面，而白质连接组主要由髓磷脂作为其主要结构成分构成，这在模拟人类神经疾病时带来了严峻挑战。鉴于髓磷脂在病理学中的差异和核心作用，对当代研究中使用的啮齿动物模型进行全面重新评估至关重要，同时要谨慎选择、优化或从头开发能够忠实地重现人类白质疾病的模型。在本综述中，我们总结了现有啮齿动物模型的优缺点，强调它们在理解自身免疫性、神经退行性、血管性、围产期、创伤性、感染性和遗传性疾病等脱髓鞘病理方面的贡献。我们还概述了使用其他物种和人类干细胞的白质疾病模型。随后，我们讨论了白质生物学中可能限制转化相关性的关键种间差异，同时强调啮齿动物模型如何增强我们对各种病理状况的理解。最后，我们概述了通过先进的基因工程、人源化微环境和多模态表型分析来优化啮齿动物模型的策略，目标是逐步改进现有模型，以提高其临床前转化潜力。
