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HPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease

ABSTRACT: hPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease

PROVIDER: PRJNA819999 | ENA |

REPOSITORIES: ENA

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hPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease [ATAC-seq]

Project description:The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT and to GDF11 to enable posterior patterning and transition from posterior trunk to sacral NC identity respectively. Using a SOX2::H2B-tdTomato/ T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting novel opportunities in the treatment of severe forms of Hirschsprung’s disease.

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hPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease [ATAC-seq]

Project description:hPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease [ATAC-seq]

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Analysis of gene expression in Sox10 Dom mutant sacral neural crest cells

Project description:Hirschsprung’s disease (HSCR) is a congenital disease which is characterized by the reduction or absence of neurons and glial cells in the enteric nervous system (ENS). Failure of neural crest cells (NCCs) to colonize the gut during the embryonic development has been considered as one of the possible causes of the disease. In this study, the migration and gene expression of sacral NCCs from the spontaneous mouse mutant Dominant megacolon (Dom) which is a HSCR animal model expressing a mutated transcription factor Sox10, were analyzed in order to identify candidate genes which may possibly affect the NCC migration in the mutant.

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Transcriptomic Profiling of Vagal and Sacral Level Neural Crest Cell from Mouse Embryos Using Next Generation Sequencing

Project description:The ENS of vertebrates develops from neural crest cell (NCC) deriving from mainly the vagal neural crest, while NCCs from the sacral level to a less extent. In mouse embryos, the vagal NCCs emigrate from the neural tube adjacent to the somite level from 1-7 at Embryonic day (E)9.0, and sacral NCCs emigrate from the neural tube adjacent to the level of somites caudal to somite 24 in the mouse (in the chick, caudal to somite 28) at E9.5. The spatial difference in cell colonization between vagal and sacral NCCs is that vagal NCCs completely colonize the whole gut, while the distribution of sacral NCCs is only restricted to the hindgut segment. To determine the differences between these two groups of cells, we isolated vagal and sacral NCCs by neural tube explant culture and then performed high-throughput RNA-seq to examine the transcriptional variation. We analyzed that differentially expressed genes (DEGs) by gene ontology (GO) analysis in which the DEGs were enriched in cell adherin, proliferation, transcriptional regulation, et al. This study might help to explore the underlying basis for the different cell behaviors between vagal and sacral NCCs during mouse embryonic development.

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hPSC-derived Sacral Neural Crest Enables Rescue in a Severe Model of Hirschsprung’s Disease

Project description:This SuperSeries is composed of the SubSeries listed below.

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