Enteric Glia

The enteric nervous system (ENS) consists of interconnected networks of neurons and glia organised into ganglia within distinct plexuses. The myenteric (Auerbach’s) plexus lies between the longitudinal and circular muscle layers. The submucosal plexus, located in the submucosa, can be further subdivided into outer (Meissner’s) and inner (Henle’s) submucosal plexuses in humans, with Henle’s plexus situated most closely to the mucosa.

Enteric glial cells (EGCs) are the most abundant cell type in the ENS, outnumbering neurons approximately four-fold in mouse and six-fold in human (Rosenberg and Rao, 2021). They form an extensive network spanning ganglionated and extra-ganglionic regions, closely associating with neuronal somata in myenteric and submucosal plexuses, as well as with nerve fibres in the muscle and mucosa (Rosenberg and Rao, 2021). EGCs also localise in epithelial crypt bases, suggesting roles in barrier regulation (Baghdadi et al., 2022).

EGCs are distinguished from Schwann cells by their unique expression of GFAP, lack of axon myelination and basal lamina formation. However, they share a neural crest origin and molecular features with Schwann cell precursors (SCPs) and converge on a similar phenotype when exposed to the same factors in vitro (Dulac and le Douarin, 1991), indicating that there may be a functional overlap between these peripheral glial cell populations. In addition, recent work has identified Schwann-like enteric glia located in extraganglionic regions, which are molecularly distinct from glia within ganglia (Windster et al., 2025). The existence of these populations highlights substantial heterogeneity within the EGC compartment, likely arising from both distinct developmental origins and niche-specific functional specialisation across the intestinal wall (Santhosh et al., 2024).

Morphologically, murine EGCs are classified into four subtypes (Boesmans et al., 2015):

• Type I (protoplasmic): star-shaped, intra-ganglionic.
• Type II (fibrous): aligned with interganglionic nerve fibres.
• Type III: multipolar cells in the lamina propria.
• Type IV: bipolar cells associated with muscle layers.

Molecularly, EGCs express canonical markers including GFAP, S100β, Sox10, Sox2, Plp1, and B-FABP. Single-cell and single-nucleus transcriptomic studies (e.g. Zeisel et al. 2018, Drokhlyansky et al. 2020) have identified multiple glial subtypes across species and developmental stages, including disease-associated states. Although there is no current consensus classification and it remains unclear whether transcriptional subtypes represent stable functional identities or context-dependent states, recent studies have begun to link spatially distinct populations, such as ganglionic versus extraganglionic glia, with functional specialisation, suggesting that enteric glial heterogeneity reflects both anatomical location and context-dependent functional adaptation (Windster et al., 2025; Muppirala et al., 2026). This remains an active and evolving area of research.

EGCs play diverse roles in ENS homeostasis:

• Structural support & mechanosensation: EGCs form scaffold stabilising neuronal networks and respond to mechanical stimuli via Ca²⁺-signalling and induction of activity-dependent genes (e.g. c-fos) (Gulbransen and Sharkey, 2012).
• Neuron-glia signalling: EGCs respond to neurotransmitters (e.g. ACh) with Ca²⁺-transients and release gliotransmitters such as ATP and GABA, modulating neuronal excitability and motility. EGC expression of glutamine synthetase, NO precursors, GABA transporters, and ion channels, contribute to support roles in neurotransmission regulation (Gulbransen and Sharkey, 2012).
• Neuronal maintenance: Ablation studies demonstrate that EGCs are required for neuronal survival, normal motility, and maintenance of neuronal subtype balance (Gulbransen et al., 2012).
• Immune function & barrier integrity: EGCs release cytokines, recruit immune cells (macrophages and T cells), and support epithelial and vascular integrity. Loss of EGCs leads to inflammation and barrier disruption. During infection, EGCs undergo gliosis and activate IFNγ-dependent immune-regulatory programmes (Progatzky et al., 2021; Progatzky and Pachnis, 2022).
• Neurogenic potential: EGCs retain progenitor-like properties, giving rise to neurons in response to injury and inflammation in vivo. Lineage tracing studies have shown that in some models (e.g. zebrafish) EGC-derived neurogenesis occurs at homeostasis (McCallum et al., 2020). Adult murine EGCs can also be induced in-vitro to give rise to mature enteric neurons under defined conditions. This neurogenesis recapitulates that occurring during development in-vivo, and involves activation of transcriptional programmes resembling those of early ENS progenitors (Laddach et al., 2023). In vitro EGC-derived neurons are capable of firing action potentials and forming synaptic connections, resembling native enteric neurons. Thus, EGC based cultures may be a promising model for studying enteric neurogenesis, and a potential source for cell-based therapies.

A major future challenge is linking EGC transcriptional heterogeneity to defined functional glial roles across physiological and pathological contexts.

Text authored by Maryam Rahim¹, Fränze Progatzky², Helen Cox³

¹ Hong lab, UKDRI at UCL, ² The Kennedy Institute of Rheumatology, University of Oxford, ³ Wolfson Sensory Pain and Regeneration Centre (SPaRC), King’s College London

References:

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Available at: https://doi.org/10.1016/j.stem.2021.10.004

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Available at: https://doi.org/10.1002/glia.22746

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Available at: https://doi.org/10.1016/J.CELL.2020.08.003

Dulac C. & Le Douarin N.M. (1991). ‘Phenotypic plasticity of Schwann cells and enteric glial cells in response to the microenvironment’, PNAS, 88(14), pp. 6358-62.
Available at: https://doi.org/10.1073/pnas.88.14.6358

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Available at: https://doi.org/10.1038/nm.2679

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Available at: https://doi.org/10.1038/s41467-023-41492-3

McCallum, S. et al. (2020) ‘Enteric glia as a source of neural progenitors in adult zebrafish’, eLife, 9, pp. 1–66.
Available at: https://doi.org/10.7554/ELIFE.56086

Muppirala, A.N. et al. (2026) ‘Tachykinin signaling defines distinct populations of glia in the enteric nervous system’, Neuron, 114(6), pp. 1066-1082.e8.
Available at: https://doi.org/10.1016/j.neuron.2025.11.030

Progatzky, F. et al. (2021) ‘Regulation of intestinal immunity and tissue repair by enteric glia’, Nature 2021 599:7883, 599(7883), pp. 125–130.
Available at: https://doi.org/10.1038/s41586-021-04006-z

Progatzky, F. and Pachnis, V. (2022) ‘The role of enteric glia in intestinal immunity’, Current Opinion in Immunology, 77, p. None.
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Rosenberg, H.J. and Rao, M. (2021) ‘Enteric glia in homeostasis and disease: From fundamental biology to human pathology’, iScience, 24(8), p. 102863.
Available at: https://doi.org/10.1016/j.isci.2021.102863

Santhosh, S. et al. (2024) ‘From diversity to disease: unravelling the role of enteric glial cells’, Frontiers in Immunology, 15, p. 1408744.
Available at: https://doi.org/10.3389/fimmu.2024.1408744

Windster, J.D. et al. (2025) ‘Human Enteric Glia Diversity in Health and Disease: New Avenues for the Treatment of Hirschsprung Disease’, Gastroenterology, 168(5), pp. 965-979.e12.
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