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.

溶酶体贮积病（LSD）是由溶酶体中的缺陷酶引起的一组代谢先天性错误，导致未降解底物的积累。LSDs揭示了许多特征性细胞特征，包括异常的自噬和线粒体功能异常。

诱导多能干细胞（iPSC）的发展极大地促进了对LSD的研究，特别是关于基于大分子（如鞘脂在溶酶体中的储存）阐明疾病病因的新机会。由LSD患者（LSD-iPSC）制成的iPSC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，从而提供了探索疾病发病机理和测试治疗策略的新工具。异常积累的底物会损害LSD-iPSC衍生的神经元的自噬，线粒体和突触功能。通过治疗候选药物减少积累，改善了LSD-iPSC衍生的神经元功能。此外，iPSC技术可以帮助探查基因表达，LSD的蛋白质组学和代谢组学。此外，LSD-iPSCs中的基因修复和致病基因中新突变的产生可用于了解致病基因的特定作用以及其他遗传因素对这些表型的贡献。此外，作为疾病模型的iPSC派生类器官的发展弥合了使用细胞系和体内动物模型。但是，iPSC研究中存在一些可再现性问题，包括遗传和表观遗传异常，例如染色体异常，DNA突变和通过甲基化进行的基因修饰。在这篇综述中，我们介绍了使用选定的LSD-iPSC收集的疾病和治疗概念，讨论了iPSC的研究局限性，并设定了我们未来的研究远景。预期此类研究将进一步为LSD提供信息并产生见解，并且在研究和临床实践中非常重要。