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Single Cell RNA-sequencing analysis of the juvenile and embryonic mouse enteric nervous system (ENS) of the small intestine

ABSTRACT: The study aimed to make a molecular definition of myenteric neuron classes in the mouse small intestine and describe their differentiation from enteric stem cells during embryogenesis. Method: We performed single cell RNA-sequencing of enteric neurons from small intestine at the juvenile stage (postnatal day (P)21) and ENS cells from the small intestine at embryonic day (E)15.5 and E18.5. We confirmed novel marker genes for all classes using immunohistochemistry and characterised the morphology/axons of three of newly discovered ENS neuron types. Results: 12 unique enteric neuron classes (ENC1-12) were identified and confirmed in native tissue by histochemical methods. The communication machinery (ligand, receptors, adhesion molecules), axonal patterns and morphologies were presented to infer functional roles of the ENCs. Analysis of embryonic transcriptomes revealed that enteric stem cells differentiate into two neuronal branches, that successively diversify into ENC1-7 and ENC8-12, respectively. Conclusion: Utilizing single cell RNA-sequencing we conclude that murine small intestine consists of 12 major myenteric classes that emerge through a step-wise fashion during embryonic development. Reference: Morarach, Mikhailova et al., 2020. BioRxiv 2020.03.02.955757

ORGANISM(S): Mus musculus

PROVIDER: GSE149524 | GEO | 2020/09/18

REPOSITORIES: GEO

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Project description:Besides symptoms caused by central nervous system (CNS) lesions, the majority of patients with multiple sclerosis (MS) also exhibit gastrointestinal dysfunction that has frequently been noted, but was not directly linked to the autoimmune etiology of the disease.We studied the enteric nervous system (ENS) in a murine model of MS by histology and electron microscopy. Serum IgG against enteric neurons and enteroglia was measured by ELISA and binding to the ENS was confirmed by immunohistochemistry. Target antigens were identified by mass spectrometry. Gastrointestinal dysfunction was determined by measuring dye transit time. RNA expression profiling was conducted with small intestines of MP4-immunized and control-immunized mice. Data from the mouse model were confirmed in MS patients by immunohistochemistry of the ENS in bowel resectates. In addition, ELISA was performed on plasma samples to detect antibodies against four specific target antigens as identified in the mouse model. ENS degeneration was evident already before the onset of clinical disease in the mouse model. Pathology was predominantly antibody-mediated and caused a significant decrease in gastrointestinal transit, which was associated with severe gliosis of the ENS. Unlike the dense infiltrates that developed in the perivascular compartments of the CNS of MP4-immunized mice, the infiltrates in the ENS consisted of single cells scattered throughout the tissue. RNA expression profiling could support these results, as the expression of inflammatory markers in the small intestine was similar between MP4-immunized and HEL-immunized mice. We identified four specific target antigens derived from enteric neurons and/or enteroglia. Antibodies against all four target antigens were present in MS patients. MS patients also showed gliosis and signs of ENS degeneration in the small intestine. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and the ENS in MS. The presence of ENS pathology prior to CNS degeneration introduces entirely novel ways to explain MS etiology and immunopathogenesis.

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Single Cell RNA-sequencing analysis of the juvenile and embryonic mouse enteric nervous system (ENS) of the small intestine

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