scholarly journals Development, Diversity, and Neurogenic Capacity of Enteric Glia

Author(s):  
Werend Boesmans ◽  
Amelia Nash ◽  
Kinga R. Tasnády ◽  
Wendy Yang ◽  
Lincon A. Stamp ◽  
...  

Enteric glia are a fascinating population of cells. Initially identified in the gut wall as the “support” cells of the enteric nervous system, studies over the past 20 years have unveiled a vast array of functions carried out by enteric glia. They mediate enteric nervous system signalling and play a vital role in the local regulation of gut functions. Enteric glial cells interact with other gastrointestinal cell types such as those of the epithelium and immune system to preserve homeostasis, and are perceptive to luminal content. Their functional versatility and phenotypic heterogeneity are mirrored by an extensive level of plasticity, illustrated by their reactivity in conditions associated with enteric nervous system dysfunction and disease. As one of the hallmarks of their plasticity and extending their operative relationship with enteric neurons, enteric glia also display neurogenic potential. In this review, we focus on the development of enteric glial cells, and the mechanisms behind their heterogeneity in the adult gut. In addition, we discuss what is currently known about the role of enteric glia as neural precursors in the enteric nervous system.

2021 ◽  
Author(s):  
Richard A Guyer ◽  
Sukhada Bhave ◽  
Rhian Stavely ◽  
Ryo Hotta ◽  
Nicole Bousquet ◽  
...  

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.


Development ◽  
1993 ◽  
Vol 117 (1) ◽  
pp. 59-74 ◽  
Author(s):  
P. F. Copenhaver

The enteric nervous system (ENS) of the moth, Manduca sexta, consists of two primary cellular domains and their associated nerves. The neurons of the anterior domain occupy two small peripheral ganglia (the frontal and hypocerebral ganglia), while a second population of neurons occupies a branching nerve plexus (the enteric plexus) that spans the foregut-midgut boundary. Previously, we have shown these two regions arise by separate programs of neurogenesis: cells that form the anterior enteric ganglia are generated from three discrete proliferative zones that differentiate within the foregut epithelium. In contrast, the cells of the enteric plexus (the EP cells) emerge from a neurogenic placode within the posterior lip of the foregut. Both sets of neurons subsequently undergo an extended period of migration and reorganization to achieve their mature distributions. We now show that prior to the completion of neurogenesis, an additional class of precursor cells is generated from the three proliferative zones of the foregut. Coincident with the onset of neuronal migration, this precursor class enters a phase of enhanced mitotic activity, giving rise to a population of cells that continue to divide as the ENS matures. Using clonal analyses of individual precursors, we demonstrate that the progeny of these cells become distributed along the same pathways taken by the migratory neurons; subsequently, they contribute to an ensheathing layer around the branches of the enteric plexus and the enteric ganglia. We conclude that this additional precursor class, which shares a common developmental origin with the enteric neurons, gives rise to a distinct population of peripheral glial cells. Moreover, the distribution of enteric glial cells is achieved by their migration and differentiation along the same pathways that are formed during the preceding phases of neuronal migration.


2018 ◽  
Vol 315 (1) ◽  
pp. G1-G11 ◽  
Author(s):  
Camille Pochard ◽  
Sabrina Coquenlorge ◽  
Marie Freyssinet ◽  
Philippe Naveilhan ◽  
Arnaud Bourreille ◽  
...  

Gone are the days when enteric glial cells (EGC) were considered merely satellites of enteric neurons. Like their brain counterpart astrocytes, EGC express an impressive number of receptors for neurotransmitters and intercellular messengers, thereby contributing to neuroprotection and to the regulation of neuronal activity. EGC also produce different soluble factors that regulate neighboring cells, among which are intestinal epithelial cells. A better understanding of EGC response to an inflammatory environment, often referred to as enteric glial reactivity, could help define the physiological role of EGC and the importance of this reactivity in maintaining gut functions. In chronic inflammatory disorders of the gut such as Crohn’s disease (CD) and ulcerative colitis, EGC exhibit abnormal phenotypes, and their neighboring cells are dysfunctional; however, it remains unclear whether EGC are only passive bystanders or active players in the pathophysiology of both disorders. The aim of the present study is to review the physiological roles and properties of EGC, their response to inflammation, and their role in the regulation of the intestinal epithelial barrier and to discuss the emerging concept of CD as an enteric gliopathy.


2019 ◽  
Vol 110 (1-2) ◽  
pp. 139-146 ◽  
Author(s):  
Claude Knauf ◽  
Anne Abot ◽  
Eve Wemelle ◽  
Patrice D. Cani

The gut-brain axis is of crucial importance for controlling glucose homeostasis. Alteration of this axis promotes the type 2 diabetes (T2D) phenotype (hyperglycaemia, insulin resistance). Recently, a new concept has emerged to demonstrate the crucial role of the enteric nervous system in the control of glycaemia via the hypothalamus. In diabetic patients and mice, modification of enteric neurons activity in the proximal part of the intestine generates a duodenal hyper-contractility that generates an aberrant message from the gut to the brain. In turn, the hypothalamus sends an aberrant efferent message that provokes a state of insulin resistance, which is characteristic of a T2D state. Targeting the enteric nervous system of the duodenum is now recognized as an innovative strategy for treatment of diabetes. By acting in the intestine, bioactive gut molecules that we called “enterosynes” can modulate the function of a specific type of neurons of the enteric nervous system to decrease the contraction of intestinal smooth muscle cells. Here, we focus on the origins of enterosynes (hormones, neurotransmitters, nutrients, microbiota, and immune factors), which could be considered therapeutic factors, and we describe their modes of action on enteric neurons. This unsuspected action of enterosynes is proposed for the treatment of T2D, but it could be applied for other therapeutic solutions that implicate communication between the gut and brain.


2001 ◽  
Vol 280 (6) ◽  
pp. G1163-G1171 ◽  
Author(s):  
A. Rühl ◽  
S. Franzke ◽  
S. M. Collins ◽  
W. Stremmel

As yet, little is known about the function of the glia of the enteric nervous system (ENS), particularly in an immune-stimulated environment. This prompted us to study the potential of cultured enteroglial cells for cytokine synthesis and secretion. Jejunal myenteric plexus preparations from adult rats were enzymatically dissociated, and enteroglial cells were purified by complement-mediated cytolysis and grown in tissue culture. Cultured cells were stimulated with recombinant rat interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, and IL-6 mRNA expression and secretion were assessed using RT-PCR and a bioassay, respectively. Stimulation with TNF-α did not affect IL-6 mRNA expression, whereas IL-1β stimulated IL-6 mRNA and protein synthesis in a time- and concentration-dependent fashion. In contrast, IL-6 significantly and dose-dependently suppressed IL-6 mRNA expression. In summary, we have presented evidence that enteric glial cells are a potential source of IL-6 in the myenteric plexus and that cytokine production by enteric glial cells can be regulated by cytokines. These findings strongly support the contention that enteric glial cells act as immunomodulatory cells in the enteric nervous system.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Timna Inlender ◽  
Einat Nissim-Eliraz ◽  
Rhian Stavely ◽  
Ryo Hotta ◽  
Allan M. Goldstein ◽  
...  

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.


2020 ◽  
Vol 318 (2) ◽  
pp. G254-G264
Author(s):  
Jean-Baptiste Cavin ◽  
Hailey Cuddihey ◽  
Wallace K. MacNaughton ◽  
Keith A. Sharkey

The small intestine regulates barrier function to absorb nutrients while avoiding the entry of potentially harmful substances or bacteria. Barrier function is dynamically regulated in part by the enteric nervous system (ENS). The role of the ENS in regulating barrier function in response to luminal nutrients is not well understood. We hypothesize that the ENS regulates intestinal permeability and ion flux in the small intestine in response to luminal nutrients. Segments of jejunum and ileum from mice were mounted in Ussing chambers. Transepithelial electrical resistance (TER), short-circuit current ( Isc), and permeability to 4-kDa FITC-dextran (FD4) were recorded after mucosal stimulation with either glucose, fructose, glutamine (10 mM), or 5% Intralipid. Mucosal lipopolysaccharide (1 mg/mL) was also studied. Enteric neurons were inhibited with tetrodotoxin (TTX; 0.5 μM) or activated with veratridine (10 μM). Enteric glia were inhibited with the connexin‐43 blocker Gap26 (20 μM). Glucose, glutamine, Intralipid, and veratridine acutely modified Isc in the jejunum and ileum, but the effect of nutrients on Isc was insensitive to TTX. TTX, Gap26, and veratridine treatment did not affect baseline TER or permeability. Intralipid acutely decreased permeability to FD4, while LPS increased it. TTX pretreatment abolished the effect of Intralipid and exacerbated the LPS‐induced increase in permeability. Luminal nutrients and enteric nerve activity both affect ion flux in the mouse small intestine acutely but independently of each other. Neither neuronal nor glial activity is required for the maintenance of baseline intestinal permeability; however, neuronal activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide. NEW & NOTEWORTHY Luminal nutrients and enteric nerve activity both affect ion transport in the mouse small intestine acutely, but independently of each other. Activation or inhibition of the enteric neurons does not affect intestinal permeability, but enteric neural activity is essential for the acute regulation of intestinal permeability in response to luminal lipids and lipopolysaccharide. The enteric nervous system regulates epithelial homeostasis in the small intestine in a time-dependent, region- and stimulus-specific manner.


2021 ◽  
Vol 22 (24) ◽  
pp. 13564
Author(s):  
Vu Thu Thuy Nguyen ◽  
Lena Brücker ◽  
Ann-Kathrin Volz ◽  
Julia C. Baumgärtner ◽  
Malena dos Santos Guilherme ◽  
...  

Neurodegenerative diseases such as Alzheimer’s disease (AD) have long been acknowledged as mere disorders of the central nervous system (CNS). However, in recent years the gut with its autonomous nervous system and the multitude of microbial commensals has come into focus. Changes in gut properties have been described in patients and animal disease models such as altered enzyme secretion or architecture of the enteric nervous system. The underlying cellular mechanisms have so far only been poorly investigated. An important organelle for integrating potentially toxic signals such as the AD characteristic A-beta peptide is the primary cilium. This microtubule-based signaling organelle regulates numerous cellular processes. Even though the role of primary cilia in a variety of developmental and disease processes has recently been recognized, the contribution of defective ciliary signaling to neurodegenerative diseases such as AD, however, has not been investigated in detail so far. The AD mouse model 5xFAD was used to analyze possible changes in gut functionality by organ bath measurement of peristalsis movement. Subsequently, we cultured primary enteric neurons from mutant mice and wild type littermate controls and assessed for cellular pathomechanisms. Neurite mass was quantified within transwell culturing experiments. Using a combination of different markers for the primary cilium, cilia number and length were determined using fluorescence microscopy. 5xFAD mice showed altered gut anatomy, motility, and neurite mass of enteric neurons. Moreover, primary cilia could be demonstrated on the surface of enteric neurons and exhibited an elongated phenotype in 5xFAD mice. In parallel, we observed reduced β-Catenin expression, a key signaling molecule that regulates Wnt signaling, which is regulated in part via ciliary associated mechanisms. Both results could be recapitulated via in vitro treatments of enteric neurons from wild type mice with A-beta. So far, only a few reports on the probable role of primary cilia in AD can be found. Here, we reveal for the first time an architectural altered phenotype of primary cilia in the enteric nervous system of AD model mice, elicited potentially by neurotoxic A-beta. Potential changes on the sub-organelle level—also in CNS-derived neurons—require further investigations.


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