Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Mol Cell Neurosci. 2020 Oct;108:103540. doi: 10.1016/j.mcn.2020.103540. Epub 2020 Aug 21.
Lysosomal storage diseases (LSDs) are a group of metabolism inborn errors caused by defective enzymes in the lysosome, resulting in the accumulation of undegraded substrates. Many characteristic cell features have been revealed in LSDs, including abnormal autophagy and mitochondrial dysfunction. The development of induced pluripotent stem cells (iPSCs) dramatically boosted research on LSDs, particularly regarding novel opportunities to clarify the disease etiology based on the storage of macromolecules, such as sphingolipids in lysosomes. iPSCs made from LSD patients (LSD-iPSCs) have been differentiated into neurons, endothelial cells, cardiomyocytes, hepatocytes, and macrophages, with each cell type closely resembling the primary disease phenotypes, providing new tools to probe the disease pathogenesis and to test therapeutic strategies. Abnormally accumulated substrates impaired autophagy and mitochondrial and synapse functions in LSD-iPSC-derived neurons. Reducing the accumulation with the treatment of drug candidates improved LSD-iPSC-derived neuron functions. Additionally, iPSC technology can help probe the gene expressions, proteomics, and metabolomics of LSDs. Further, gene repair and the generation of new mutations in causative genes in LSD-iPSCs can be used to understand both the specific roles of causative genes and the contributions of other genetic factors to these phenotypes. Moreover, the development of iPSC-derived organoids as disease models has bridged the gap between studies using cell lines and in vivo animal models. There are some reproducibility issues in iPSC research, however, including genetic and epigenetic abnormalities, such as chromosomal abnormalities, DNA mutations, and gene modifications via methylation. In this review, we present the disease and treatment concepts gathered using selected LSD-iPSCs, discuss iPSC research limitations, and set our future research visions. Such studies are expected to further inform and generate insights into LSDs and are important in research and clinical practice.
溶酶体贮积症（LSDs）是一组由于溶酶体中的缺陷酶导致的代谢性先天性错误，导致未降解底物的积累。在 LSDs 中已经揭示了许多特征性的细胞特征，包括异常自噬和线粒体功能障碍。诱导多能干细胞（iPSCs）的发展极大地推动了 LSDs 的研究，特别是在基于大分子（如溶酶体中的鞘脂）的储存来阐明疾病病因方面提供了新的机会。从 LSD 患者中获得的 iPSCs（LSD-iPSCs）已分化为神经元、内皮细胞、心肌细胞、肝细胞和巨噬细胞，每种细胞类型都与原发性疾病表型非常相似，为探究疾病发病机制和测试治疗策略提供了新工具。异常积累的底物会损害 LSD-iPSC 衍生神经元中的自噬和线粒体及突触功能。用候选药物治疗减少积累可改善 LSD-iPSC 衍生神经元的功能。此外，iPSC 技术可以帮助探究 LSDs 的基因表达、蛋白质组学和代谢组学。此外，在 LSD-iPSCs 中修复基因和产生新的突变，可以用来理解致病基因的具体作用以及其他遗传因素对这些表型的贡献。此外，iPSC 衍生类器官作为疾病模型的发展填补了使用细胞系和体内动物模型之间的空白。然而，iPSC 研究存在一些可重复性问题，包括遗传和表观遗传异常，如染色体异常、DNA 突变和通过甲基化的基因修饰。在这篇综述中，我们展示了使用选定的 LSD-iPSCs 收集的疾病和治疗概念，讨论了 iPSC 研究的局限性，并设定了我们未来的研究愿景。这些研究有望进一步为 LSDs 提供信息并产生新的见解，对于研究和临床实践都非常重要。
