Role of induced pluripotent stem cells in lysosomal storage diseases

Abstract

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.

Keywords: Induced pluripotent stem cell; Lysosomal storage diseases; Neuron; Pathogenesis.