Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2012; 109(44). DOI: 10.1073/pnas.1207889109
Source: PubMed


Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase gene. To model GD, we generated human induced pluripotent stem cells (hiPSC), by reprogramming skin fibroblasts from patients with type 1 (N370S/N370S), type 2 (L444P/RecNciI), and type 3 (L444P/L444P) GD. Pluripotency was demonstrated by the ability of GD hiPSC to differentiate to all three germ layers and to form teratomas in vivo. GD hiPSC differentiated efficiently to the cell types most affected in GD, i.e., macrophages and neuronal cells. GD hiPSC-macrophages expressed macrophage-specific markers, were phagocytic, and were capable of releasing inflammatory mediators in response to LPS. Moreover, GD hiPSC-macrophages recapitulated the phenotypic hallmarks of the disease. They exhibited low glucocerebrosidase (GC) enzymatic activity and accumulated sphingolipids, and their lysosomal functions were severely compromised. GD hiPSC-macrophages had a defect in their ability to clear phagocytosed RBC, a phenotype of tissue-infiltrating GD macrophages. The kinetics of RBC clearance by types 1, 2, and 3 GD hiPSC-macrophages correlated with the severity of the mutations. Incubation with recombinant GC completely reversed the delay in RBC clearance from all three types of GD hiPSC-macrophages, indicating that their functional defects were indeed caused by GC deficiency. However, treatment of induced macrophages with the chaperone isofagomine restored phagocytosed RBC clearance only partially, regardless of genotype. These findings are consistent with the known clinical efficacies of recombinant GC and isofagomine. We conclude that cell types derived from GD hiPSC can effectively recapitulate pathologic hallmarks of the disease.

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    • "For Sanfilippo B syndrome, patient-derived neurons presented storage vesicles and Golgi disorganization (Lemonnier et al., 2011). In the case of Gaucher disease, iPSC-derived macrophages showed impaired lysosomal function and red blood cell clearance, recapitulating the hallmarks of the disease in this cell type, which could be reverted after administration of the recombinant enzyme (Panicker et al., 2012). Moreover, Gaucher disease-specific macrophages and neurons displayed low enzyme activity that could be partially rescued using small compounds with chaperone activity (Tiscornia et al., 2013); and dopaminergic neurons accumulated glucosylceramide and a-synuclein and showed autophagy and lysosomal defects and dysregulation of calcium homeostasis , all of which could be reverted after gene correction (Schöndorf et al., 2014). "
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