Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors

Abstract

Background: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the IDUA gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. Methods: To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both IDUA alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of IDUA deficiency on gene expression (340 genes with an FDR <0.05). Conclusions: Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients.

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

“…Overall, these results strongly supported the idea that one can nicely characterize and distinguish different forms of the same disorder, by evaluating iPSC-derived models, as they recapitulate at the subcellular level the severity seen in patients [126]. Four years later, another interesting study was conducted by Lito S. et al [127] focusing on the most severe form of the disease alone (Hurler). In that paper, besides reprogramming dermal fibroblasts into iPSCs and generating NSCs, the authors went one step beyond and created an isogenic control from these iPSCs by reestablishing IDUA expression to avoid any type of variability that could emerge from the comparison with iPSC control cell lines derived from other individuals.…”

“…In general, these migration defects and gene expression changes seen in patients affected by monogenic diseases are associated with a cause-effect relationship, where the genotype presents as a cause and the phenotype as an effect. However, based on these results, the authors purpose that the reverse may also occur, presenting a bidirectional pattern [127].…”

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

“…Four years later, another interesting study was conducted by Lito S. et al [ 66 ] focusing on the most severe form of the disease alone (Hurler). In that paper, in addition to reprogramming dermal fibroblasts into iPSCs and generating NSCs, the authors went one step beyond and created an isogenic control from these iPSCs by re-establishing IDUA expression to avoid any type of variability that could emerge from the comparison with control iPSC lines derived from other individuals.…”

“…In general, these migration defects and gene expression changes seen in patients affected by monogenic diseases are associated with a cause–effect relationship, where the genotype presents as a cause and the phenotype as an effect. However, based on these results, the authors proposed that the reverse may also occur, presenting a bidirectional pattern [ 66 ].…”