Enteric glia regulate Paneth cell secretion and intestinal microbial ecology
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PROVIDER: PRJNA1178611 | ENA |
REPOSITORIES: ENA
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Project description:Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
2024-12-01 | GSE280442 | GEO
Project description:To identify the gene expression profile of enteric glia and assess the transcriptional similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oli- godendrocytes, although there is no evidence of myelination in the murine ENS. Total RNA expression profiles of PLP1 expressing enteric glial cells (GFP+) and non-glial cells (GFP-negative) were obtained from the ileum and colon of juvenile PLP1-eGFP transgenic mice.
2015-09-01 | E-GEOD-72560 | biostudies-arrayexpress
Project description:BACKGROUND Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS With ~4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glia reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
2023-11-15 | GSE198889 | GEO
Project description:To identify the gene expression profile of enteric glia and assess the transcriptional similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oli- godendrocytes, although there is no evidence of myelination in the murine ENS.
2015-09-01 | GSE72560 | GEO
Project description:Enteric glia are the predominant cell type in the enteric nervous system yet their identities and roles in gastrointestinal function are not well classified. Using our optimized single nucleus RNA-sequencing method, we identified distinct molecular classes of enteric glia and defined their morphological and spatial diversity. Our findings revealed a functionally specialized biosensor subtype of enteric glia that we call “hub cells.” Deletion of the mechanosensory ion channel PIEZO2 from adult enteric glial hub cells, but not other subtypes of enteric glia, led to defects in intestinal motility and gastric emptying in mice. These results provide insight into the multifaceted functions of different enteric glial cell subtypes in gut health and emphasize that therapies targeting enteric glia could advance the treatment of gastrointestinal diseases.
2023-09-08 | GSE232703 | GEO
Project description:Glial cells have been proposed as an endogenous source of progenitors for the treatment of neural deficits. However, the cellular and molecular mechanisms underpinning the neurogenic potential of certain populations of adult glial cells, are not known. Using single cell transcriptomic profiling, we show here that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition during development along a linear default differentiation trajectory that allows them to retain neurogenic potential while acquiring a gene expression profile associated with their role in neuronal support and immunomodulation. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a novel cell culture system of enteric neurogenesis and a gut injury model, demonstrated that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the dynamic regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits.
2023-07-31 | GSE239305 | GEO
Project description:Enteric glia cells (EGCs) are highly plastic and has been shown to give rise to neurons in adult gut upon injury to the enteric nervous system (ENS). To better characterise the dynamic molecular changes associated with EGC activation and its subsequent neurogenic differentation trajectory, we performed bulk RNAseq experiments from FACS sorted lineage-labelled cells (Sox10::CreERT2;R26-tdTomato) from adult small intestines (DIV0) and compared their transcriptomic profiles to cultured FACS sorted tdTomato+ cells from days in vitro (DIV) 4, 11 and 20, which were subjected to a protocol to support neurogenesis in culture.
2023-07-26 | GSE160196 | GEO
Project description:Glial cells have been proposed as an endogenous source of progenitors for the treatment of neural deficits. However, the cellular and molecular mechanisms underpinning the neurogenic potential of certain populations of adult glial cells, are not known. Using single cell transcriptomic profiling, we show here that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition during development along a linear default differentiation trajectory that allows them to retain neurogenic potential while acquiring a gene expression profile associated with their role in neuronal support and immunomodulation. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a novel cell culture system of enteric neurogenesis and a gut injury model, demonstrated that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the dynamic regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits.
2023-07-26 | GSE237970 | GEO
Project description:Glial cells have been proposed as an endogenous source of progenitors for the treatment of neural deficits. However, the cellular and molecular mechanisms underpinning the neurogenic potential of certain populations of adult glial cells, are not known. Using single cell transcriptomic profiling, we show here that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition during development along a linear default differentiation trajectory that allows them to retain neurogenic potential while acquiring a gene expression profile associated with their role in neuronal support and immunomodulation. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a novel cell culture system of enteric neurogenesis and a gut injury model, demonstrated that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the dynamic regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits.
2023-07-23 | GSE237713 | GEO
Project description:Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here, we uncover pivotal roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus (H. poly) leads to enteric gliosis and upregulation of the interferon gamma (IFN-γ) gene signature. Single-cell transcriptomics of tunica muscularis (TM) showed that glia-specific abrogation of IFN-γ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. In addition, disruption of the IFN-γ-EGC signaling axis enhanced the inflammatory and granulomatous response of TM to helminths. Mechanistically, we show that upregulation of Cxcl10 is an early immediate response of EGCs to IFN-γ signaling and provide evidence that this chemokine and the downstream amplification of IFN-γ signaling in the TM are required for a measured inflammatory response to helminths and resolution of granulomatous pathology. Our study demonstrates that IFN-γ signaling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN-γ-EGC-Cxcl10 axis in immune response and tissue repair following infectious challenge. To characterize the response of enteric glia to helminth infection, we performed bulk RNAseq of tdT+ cells (=EGCs) and tdT- cells (=non-glia cells) from the TM of naïve and H. poly-infected Sox10CreERT2;Rosa26tdTomato mice.
2021-08-25 | GSE182708 | GEO