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.

Download full-text


Available from: Tea Soon Park
  • Source
    • "Neurological Huntington's Disease (HD) Fibroblasts[69]Parkinson's Disease (PD) Fibroblasts[70]Familial Alzheimer's Disease (AD) Fibroblasts[71]Frontotemporal Dementia (FTD) Fibroblasts[72]Amyotrophic Lateral Sclerosis (ALS) Fibroblasts737475Spinocerebellar Ataxia Type 2 (SCA 2) Fibroblasts[76]Machado-Joseph Disease (MJD) Fibroblasts[77]Rett Syndrome Fibroblasts[78]Cardiac/ Muscular LEOPARD Syndrome Fibroblasts[79]Duchenne Muscular Dystrophy (DMD) Fibroblasts[80]Long QT Syndrome Fibroblasts[81]Pompe Disease Fibroblasts[82]Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Fibroblasts[83,84]Dilated Cardiomyopathy (CMD) Fibroblasts[85]Barth Syndrome (BTHS) Fibroblasts[86]Friedreich Ataxia Fibroblasts[87]Metabolic Alpha-1 Antitrypsin Deficiency (A1ATD) Fibroblasts[88]Familial Hypercholesterolemia (FH) Fibroblasts[89]Glycogen Storage Disease Type 1a (GSD1a) Fibroblasts[90]Glycogen Storage Disease Type 1b (GSD1b) Fibroblasts, Hepatic Cells (nonparenchymal)[91]Type 1 Diabetes Fibroblasts[92]Gauchers Disease (GD) Fibroblasts[93]Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) Fibroblasts[94]Carnitine Palmitoyltransferase II (CPT II) Fibroblasts[95]Eye/Retina Usher Syndrome (USH) Keratinocytes[96]Retinitis Pigmentosa (RP) Fibroblasts979899Leber Congenital Amaurosis (LCA) Fibroblasts[100]Gyrate Atrophy (GA) Fibroblasts[101]Best Vitelliform Macular Dystrophy (BVMD) Fibroblasts[102]Age Related Macular Degeneration (AMD) T-Cells[103]Blood Shwachman-Diamond Syndrome (SDS) Fibroblasts[104]Dyskeratosis Congenita (DKC) Fibroblasts[105]Familial Platelet Disorder (FPD) Peripheral T Cells[106]Sickle Cell Disease MSCs[107,108]β-Thalassemia Fibroblasts[109]Myeloproliferative Disorders (MPDs) Peripheral Blood CD34 + Cells[18]Myelodysplastic Syndromes (MDS) Hematopoietic Cells[17][20,116]Juvenile Myelomonocytic Leukemia (JML) Primary JML Cells[117]Gastrointestinal Cancer Gastrointestinal Cancer Cells[21]Li-Fraumeni Syndrome (LFS) Fibroblasts[118]Other Hutchinson Gilford Progeria Fibroblasts[119]Primary Ovarian Insufficiency (POI) Fibroblasts[120]Hermansky-Pudlak (HP) Fibroblasts[121]Chediak-Higashi (CH) Fibroblasts[121]iPSCs technology is providing exciting new opportunities in cardiovascular research by creating platforms to study the mechanisms of disease pathogenesis that could lead to new therapies. For instance, iPSCs derived from patients with LEOPARD syndrome, an autosomal-dominant developmental disorder caused by mutation in the PTPN11 gene encoding the SHP2 phosphatase, can recapitulate the hypertrophic cardiomyopathy phenotype of this disease[81]. "

    Full-text · Article · Jan 2016 · International Journal of Molecular Sciences
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration.
    Full-text · Article · Sep 2015 · Stem Cell Reports
  • [Show abstract] [Hide abstract]
    ABSTRACT: A thorough sort of the human drugs approved by the European Medicines Agency (EMA) between its establishment in 1995 until June 2012 is presented herein with a focus on biologically-derived pharmaceuticals. Over 200 (33%) of the 640 approved therapeutic drugs are derived from natural sources, produced via recombinant DNA technology, or generated through virus propagation. A breakdown based on production method, type of molecule and therapeutic category is presented. Current EMA approvals demonstrate that mammalian cells are the only choice for glycoprotein drugs, with Chinese hamster ovary cells being the dominant hosts for their production. On the other hand, bacterial cells and specifically Escherichia coli are the dominant hosts for protein-based drugs, followed by the yeast Saccharomyces cerevisiae. The latter is the dominant host for recombinant vaccine production, although egg-based production is still the main platform of vaccine provision. Our findings suggest that the majority of biologically-derived drugs are prescribed for cancer and related conditions, as well as the treatment of diabetes. The approval rate for biologically-derived drugs shows a strong upward trend for monoclonal antibodies and fusion proteins since 2009, while hormones, antibodies and growth factors remain the most populous categories. Despite a clear pathway for the approval of biosimilars set by the EMA and their potential to drive sales growth, we have only found approved biosimilars for three molecules. In 2012 there appears to be a slow-down in approvals, which coincides with a reported decline in the growth rate of biologics sales.
    No preview · Article · Dec 2012 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
Show more