The Human and Mouse Enteric Nervous System at Single-Cell Resolution

AbstractIn mammals, neural crest cells populate the gut and form the enteric nervous system (ENS) early in embryogenesis. Although the basic ENS structure is highly conserved across species, we show important differences between mice and humans relating to the prenatal and postnatal development of mucosal enteric glial cells (mEGC), which are essential ENS components. We confirm previous work showing that in the mouse mEGCs are absent at birth, and that their appearance and homeostasis depends on postnatal colonization by microbiota. In humans, by contrast, a network of glial cells is already present in the fetal gut. Moreover, in xenografts of human fetal gut maintained for months in immuno-compromised mice, mEGCs persist following treatment with antibiotics that lead to the disappearance of mEGCs from the gut of the murine host. Single cell RNAseq indicates that human and mouse mEGCs differ not only in their developmental dynamics, but also in their patterns of gene expression.

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The enteric nervous system of the human and mouse colon at a single-cell resolution

10.1101/746743 ◽

2019 ◽

Cited By ~ 7

Author(s):

Eugene Drokhlyansky ◽

Christopher S. Smillie ◽

Nicholas Van Wittenberghe ◽

Maria Ericsson ◽

Gabriel K. Griffin ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Single Cell ◽

Molecular Mechanisms ◽

Current Model ◽

Human Colon ◽

Enteric Neurons ◽

Stem Cell Maintenance ◽

Reference Map ◽

Human And Mouse

AbstractAs the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.

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The enteric nervous system of the human and mouse colon at a single-cell resolution

10.1242/prelights.14063 ◽

2019 ◽

Author(s):

Jessica Xie

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Single Cell ◽

Mouse Colon ◽

Human And Mouse

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Single-cell molecular interrogation of enteric nervous system development

Mechanisms of Development ◽

10.1016/j.mod.2017.04.151 ◽

2017 ◽

Vol 145 ◽

pp. S67

Author(s):

Khomgrit Morarach ◽

Fatima Memic ◽

Amit Zeisel ◽

Hannah Hochgerner ◽

Ulrika Marklund ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Single Cell ◽

System Development ◽

Nervous System Development ◽

Enteric Nervous System Development

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Human and Mouse Enteric Nervous System Neurosphere Transplants Regulate the Function of Aganglionic Embryonic Distal Colon

Gastroenterology ◽

10.1053/j.gastro.2008.03.035 ◽

2008 ◽

Vol 135 (1) ◽

pp. 205-216.e6 ◽

Cited By ~ 95

Author(s):

Richard M. Lindley ◽

Daniel B. Hawcutt ◽

M. Gwen Connell ◽

Sarah N. Almond ◽

Maria–Giuliana Vannucchi ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Distal Colon ◽

Human And Mouse

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Integrated single-cell analysis of enteric glial cells reveals a molecular basis for postnatal neurogenesis and its therapeutic application

10.1101/2021.08.24.457368 ◽

2021 ◽

Author(s):

Richard A Guyer ◽

Sukhada Bhave ◽

Rhian Stavely ◽

Ryo Hotta ◽

Nicole Bousquet ◽

...

Keyword(s):

Nervous System ◽

Stem Cell ◽

Enteric Nervous System ◽

Single Cell ◽

Neural Stem Cell ◽

Glial Cells ◽

Three Dimensional ◽

Enteric Neurons ◽

Open Chromatin ◽

Enteric Glial Cells

Traditional models posit that enteric neurons and glial cells represent distinct terminal lineages derived from a common neural crest precursor. This model, however, does not explain the neurogenic capability of murine postnatal enteric glial cells. To characterize the full diversity of myenteric glial cells and identify a basis for the glial-to-neuronal transition, which we demonstrate using a two-marker system, we applied single-cell RNA sequencing and single-nucleus ATAC sequencing to generate a multiomic atlas of Plp1-expressing glial cells from the small intestine of adolescent mice. We identify nine transcriptionally distinct subpopulations of enteric glial cells, including cells expressing both canonical neural stem cell genes and enteric neuronal transcriptional factors. We refer to these Plp1-positive cells with neural stem cell features as glial neuroblasts. Surprisingly, most glial cells maintain open chromatin at neuronal-associated loci, suggesting enteric glia are primed for neuronal transition. Comparison with the developing embryonic enteric nervous system shows postnatal glial cells maintain a transcriptional program closely matching embryonic neuronal progenitors. Transcription factor motif enrichment analysis and regulon analysis implicate AP-1 transcription factors in maintaining the glial neuroblast gene program. Three-dimensional cultures of postnatal enteric nervous system cells, which are enriched for glial neuroblasts and provide a niche for neuronal development, recapitulate the transcriptional changes seen during embryonic enteric neurogenesis. snATAC analysis shows chromatin closing consistent with terminal differentiation as glial cells become neurons in three-dimensional culture. In conclusion, postnatal myenteric glial cells include a neuroblast population and maintain a chromatin structure primed for neuronal fate acquisition.

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