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

Cells

Adama Sidibe¹  Bernhard Wehrle-Haller¹  Karl-Heinz Krause²  Antoine Marteyn²  Sten Ilmjarv²  Silvin Lito²  Matthias Baumgartner³  Patricie Burda³ 

[1] Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland;Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva 4, Switzerland;Division of Metabolism and Children’s Research Center, University Children’s Hospital, CH-8032 Zürich, Switzerland;

关键词: induced pluripotent stem cells;    neuronal differentiation;    disease modelling;    mucopolysaccharidosis I;    neural migration;    neurite outgrowth;   

DOI  :  10.3390/cells9122593

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown