Induced pluripotent stem cells for modeling neurological disorders

Russo, Fabiele Baldino; Cugola, Fernanda R.; Fernandes, Isabella Rodrigues; Pignatari, Graciela Conceição; Beltrão-Braga, Patrícia Cristina Baleeiro

doi:10.5500/wjt.v5.i4.209

Cited by 41 publications

(36 citation statements)

References 145 publications

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“…While potentially limiting, we showed that by modifying the cultivation protocol, the MPSII iPSC lineages could be differentiated into neurospheres. These observations suggest that IDS deficiency may, similarly to other neurological diseases, partly interfere with the fitness of the neuronal and glial precursors (Russo et al 2015). Critically however, and as previously documented in IDS deficient murine neuronal stem cells (Fusar Poli et al 2013), IDS deficiency does not represent a fundamental compromise to the differentiation potential of the human MPSII iPSCs.…”

Section: Discussionsupporting

confidence: 52%

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Rybová

Ledvinová

Sikora

et al. 2017

J of Inher Metab Disea

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Mucopolysaccharidosis type II (MPSII) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene (IDS, Xq28). MPSII is characterized by skeletal deformities, hearing loss, airway obstruction, hepatosplenomegaly, cardiac valvular disease, and progressive neurological impairment. At the cellular level, IDS deficiency leads to lysosomal storage of glycosaminoglycans (GAGs), dominated by accumulation of dermatan and heparan sulfates. Human induced pluripotent stem cells (iPSC) represent an alternative system that complements the available MPSII murine model. Herein we report on the reprogramming of peripheral white blood cells from male and female MPSII patients into iPSC using a non-integrating protocol based on the Sendai virus vector system. We differentiated the iPSC lines into IDS deficient and GAG accumulating β-Tubulin III neurons, GFAP astrocytes, and CNPase oligodendrocytes. The lysosomal system in these cells displayed structural abnormalities reminiscent of those previously found in patient tissues and murine IDS deficient neuronal stem cells. Furthermore, quantitative determination of GAGs revealed a moderate increase in GAG levels in IDS deficient neurons and glia. We also tested the effects of recombinant IDS and found that the exogenous enzyme was internalized from the culture media and partially decreased the intracellular GAG levels in iPSC-derived neural cells; however, it failed to completely prevent accumulation of GAGs. In summary, we demonstrate that this human iPSC based model expresses the cellular and biochemical features of MPSII, and thus represents a useful experimental tool for further pathogenesis studies as well as therapy development and testing.

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Section: Discussionsupporting

confidence: 52%

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Rybová

Ledvinová

Sikora

et al. 2017

J of Inher Metab Disea

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“…As ACh and serotonin can be released in the same fashion, gene and cell therapies for other diseases related to ACh and serotonin, such as Alzheimer's disease, depression, schizophrenia, and syndromic autism, may utilize ATP6V0C in the future. This approach is applicable for iPSC therapy for similar categories of diseases [72][73][74] because better recovery would be expected if iPSC contains transmitter synthesizing genes and ATP6V0C, because most of iPS cells drived from the skin fibroblasts are likely silent [27]. subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila.…”

Section: Resultsmentioning

confidence: 99%

Neurotransmitter release: vacuolar ATPase V0 sector c-subunits in possible gene or cell therapies for Parkinson’s, Alzheimer’s, and psychiatric diseases

et al. 2016

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Gene therapy or cell transplantation therapy has made great progress in recent years. We overview mediatophore as a potential medical usage for gene and transplantation therapies in the nervous system. The 16-kDa proteolipid mediatophore was shown to mediate the secretion of acetylcholine in a Ca 2+ -dependent manner. Mediatophore is known to be identical to the transmembrane c-subunit of the V0 sector of the vacuolar proton ATPase (ATP6V0C).Recent development of structural understandings reveals that ATP6V0C is not a simple pore-forming stalk enable to permeate transmitters.Therefore, it is time to review this topic revisited from the recent knowledge on ATPase.

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“…Our study, however, revealed a significant decrease in excitatory synaptic density in 16pdel neurons, suggesting that distinct mechanisms underlie cell growth and synaptogenesis. Reduced synaptic density, predominantly excitatory, has been demonstrated in several iPSC studies modeling NDDs(Russo et al, 2015) such as Rett syndrome and tuberous sclerosis. In fact, the TSC2 deficient iPSC-derived neurons show neuronal and synaptic alterations(Costa et al, 2016) that closely resemble those we found in 16pdel neurons.…”

Section: Discussionmentioning

confidence: 96%

Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder

et al. 2017

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Summary A deletion or duplication in the 16p11.2 region is associated with neurodevelopmental disorders including autism spectrum disorder and schizophrenia. In addition to clinical characteristics, carriers of the 16p11.2 copy number variant (CNV) manifest opposing neuroanatomical phenotypes, e.g. macrocephaly in deletion carriers (16pdel) and microcephaly in duplication carriers (16pdup). Using fibroblasts obtained from 16pdel and 16pdup carriers, we generated induced pluripotent stem cells (iPSCs) and differentiated them into neurons to identify causal cellular mechanisms underlying neurobiological phenotypes. Our study revealed increased soma size and dendrite length in 16pdel neurons and reduced neuronal size and dendrite length in 16pdup neurons. Functional properties of iPSC-derived neurons corroborated aspects of these contrasting morphological differences that may underlie brain size. Interestingly, both 16pdel and 16pdup neurons displayed reduced synaptic density, suggesting that distinct mechanisms may underlie brain size and neuronal connectivity at this locus.

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Induced pluripotent stem cells for modeling neurological disorders

Cited by 41 publications

References 145 publications

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Neurotransmitter release: vacuolar ATPase V0 sector c-subunits in possible gene or cell therapies for Parkinson’s, Alzheimer’s, and psychiatric diseases

Cellular Phenotypes in Human iPSC-Derived Neurons from a Genetic Model of Autism Spectrum Disorder

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