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Neural stem cells, pluripotent cells and organoids: a new window into personal human neurodevelopment| old_uid | 14363 |
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| title | Neural stem cells, pluripotent cells and organoids: a new window into personal human neurodevelopment |
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| start_date | 2017/09/25 |
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| schedule | 11h-12h |
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| online | no |
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| details | Hosted by Jean Leon Thomas |
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| summary | We have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that post-mortem and imaging studies offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) allow the direct study of gene expression and cellular phenotypes as neural cells divide and differentiate and the influence of the personal genetic background on these processes. As such, hiPSC model systems promise to bridge the gap between genomic variation and its effects on neuronal development. We investigated the extent to which hiPSC reflect authentic human neurodevelopment by comparing gene expression and gene regulatory regions between iPSC-derived telencephalic organoids and isogenic postmortem brain tissue, and mapped the organoid’s developmental stages using transcriptome datasets of prenatal, perinatal and adult brains. Analyzing and cross- comparing the genomes of prenatal brain tissue, skin-derived hiPSC, and clones of brain neuronal progenitors derived from the same human prenatal specimen, it is possible to investigate somatic mosaicism, a phenomenon by which cells develop different genomes by the accumulation of mutations throughout life. We detected ~180-400 mosaic single nucleotide variations (SNVs) per brain progenitor cell at 15-21 weeks post-conception. SNVs with a frequency of >2% in brain were shared with the spleen, revealing a pre-gastrulation origin. We calculated mutation rates of 1.3±0.15 per division per cell before gastrulation and ~8.6 per division per cell in neuronal progenitors, suggesting that neurogenesis is more mutagenic than early embryogenesis, and both periods show more mutagenesis than adulthood. We conclude that hiPSCs can be useful to elucidate the extent to which human genetic variation, both inherited and somatic, is reflected in different trajectories of early human brain development, and therefore represent a promising model for personalized diagnostics and therapeutics. |
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| responsibles | Oliviero |
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