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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199439 | GEO | 2022/07/01

REPOSITORIES: GEO

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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.

2022-07-01 | GSE199440 | GEO

Single-cell profiling coupled with lineage analysis reveals vagal and sacral neural crest contributions to the developing enteric nervous system

Project description:During development, much of the enteric nervous system (ENS) arises from the vagal neural crest that emerges from the caudal hindbrain and colonizes the entire gastrointestinal tract. However, a second contribution to the ENS comes from the sacral neural crest that arises in the caudal neural tube and populates the post-umbilical gut. By coupling single cell transcriptomics with axial-level specific lineage tracing in avian embryos, we compared the contributions of embryonic vagal and sacral neural crest cells to the pre-umbilical and post-umbilical chick ENS and the associated peripheral ganglia (the Nerve of Remak and pelvic plexuses) at embryonic day (E) 10.

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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.

2021-06-25 | GSE178834 | GEO

Axial progenitors generate trunk neural crest cells in vitro

Project description:The in vitro generation of neural crest (NC) cells from human pluripotent stem cells (hPSCs) is a valuable approach to study human NC biology and isolate NC derivatives for disease modelling/regenerative medicine applications. However, conventional differentiation protocols induce only a modest yield of NC cells corresponding to the trunk level. Here we show that trunk NC cells and, their downstream derivatives, sympathoadrenal progenitors, can be produced at a high efficiency from hPSC-derived axial progenitors, the in vitro counterparts of the posteriorly-located drivers of embryonic axis elongation. Moreover, using transcriptome analysis, we define the molecular signatures associated with the emergence of human NC cells of distinct axial identities. Collectively, our findings indicate that a post-cranial NC state is achieved through two different routes: the birth of cardiac and vagal NC is facilitated by retinoic acid-induced posteriorisation of an anterior precursor whereas a trunk fate relies on a posterior axial progenitor intermediate.

2018-08-10 | GSE109267 | GEO

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Project description:Ectoderm-derived neural crest is a transient structure arising during early embryogenesis in vertebrates. Neural crest consists of four derivatives based on their anterior- to posterior location along the body axis; cranial, vagal, trunk and sacral, respectively. We recently showed that trunk neural crest-specific gene MOXD1 functions as a tumor suppressor in trunk neural crest-derived childhood cancer form neuroblastoma and is essential for proper development of healthy adrenal glands. However, the role of MOXD1 during early embryogenesis is not known. Here, we conditionally knocked out MOXD1 in trunk neural crest cells before they become lineage-committed, using a CRISPR/Cas9 approach in chick embryos. Assessment of embryo growth showed that knockout of MOXD1 delayed development with knockout embryos being smaller. RNA sequencing of trunk-derived neural crest cells from control and knockout embryos showed enrichment of genes connected to gland development, copper ion metabolism and neuroblastoma progression. In conclusion, MOXD1 is important during early and prolonged embryonic development with effects on gland formation, possibly mediated via its role in copper metabolism.

2023-09-13 | GSE242700 | GEO

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.

2020-11-17 | GSE161579 | GEO

RNA Seq analysis of E9.5 embryonic vagal regions in Rdh10 mutants of mouse

Project description:The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate the neurons and glia that regulate gastrointestinal function. Defects in the migration, colonization or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an unknown genetic diagnosis. Therefore, it’s important to identify new genes, modifiers and environmental factors that regulate ENS development and HSCR. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit total intestinal aganglionosis, the most severe form of HSCR. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and we demonstrate that paracrine retinoid signaling is essential between E7.5-E9.5 for NCC entry into the gut. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to enter the foregut. Comparative RNA-sequencing revealed Ret-Gdnf-Gfra1-signaling which is critical for vagal NCC chemotaxis is downregulated in Rdh10 mutants and furthermore that the composition of the extracellular matrix through which NCC migrate is altered, particularly by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of HSCR.

2022-02-01 | GSE166625 | GEO

Ret loss-of-function decreases neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

Project description:The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

2021-12-30 | GSE192676 | GEO

Cumulative in-cis mutagenesis in vivo reveals various functions for CTCF sites at the mouse Hoxd cluster [ChIP-seq]

Project description:ChIP-seq analysis of CTCF wildtype in mouse embryonic posterior trunk and brain samples

2021-10-05 | GSE181383 | GEO

A Robust Method To Derive Functional Neural Crest Cells From Human Pluripotent Stem Cells

Project description:Neural crest (NC) cells contribute to the development of many complex tissues. The abnormal development of NC cells accounts for a number of congenital birth defects. Generating NC cells, and more specifically NC subpopulations such as cranial, cardiac, and trunk NC cells from human induced pluripotent stem (iPS) cells and human embryonic stem (ES) cells presents a valuable tool to model and study human NC development and disease. Here we provide a robust, efficient, and reproducible protocol for the differentiation of human iPS and ES cells into NC cells. The protocol has been validated in multiple human pluripotent stem cell lines and yields relatively pure NC cell populations in eight days. The resulting cells can be propagated and retain NC marker expression over multiple passages. The NC cells show proper cell specification and can develop into NC-derived cell lineages including smooth muscle cells, peripheral neurons, and Schwann cells. Additionally, the NC cells are functional and migrate to appropriate chemoattractants such as SDF-1, Fgf8b, BMP2, and Wnt3a. Importantly, this method generates all NC subpopulations (cranial, cardiac, and trunk) providing a great advantage to readily available NC differentiation methods.

2013-08-16 | GSE44727 | GEO

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