Advantage of Enteric Glial Cells' Plasticity and Multipotency: Comparison
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The enteric nervous system (ENS), known as the intrinsic nervous system of the gastrointestinal tract, is composed of a diverse array of neuronal and glial cell subtypes. Fascinating questions surrounding the generation of cellular diversity in the ENS have captivated ENS biologists for a considerable time, particularly with recent advancements in cell type-specific transcriptomics at both population and single-cell levels. However, the current focus of research in this field is predominantly restricted to the study of enteric neuron subtypes, while the investigation of enteric glia subtypes significantly lags behind. Despite this, enteric glial cells (EGCs) are increasingly recognized as equally important regulators of numerous bowel functions. Moreover, a subset of postnatal EGCs exhibits remarkable plasticity and multipotency, distinguishing them as critical entities in the context of advancing regenerative medicine.

  • neural crest cells
  • Schwann cells
  • enteric glial cells
  • plasticity
  • multipotency
  • enteric nervous system

1. Plasticity and Multipotency of EGCs

1.1. EGCs’ Plasticity

Once generated and integrated in the mature ENS, EGCs are not static. On the contrary, EGCs exhibit a high level of phenotypic plasticity, which wresearche rs here define by changes in molecular composition, structure and/or function. Under physiological conditions, EGCs’ plasticity is not obvious at first glance, with a single study reporting dynamic GFAP expression in murine topo-morphological Type 1 EGCs [23][1]. As recently reviewed in more detail elsewhere [20[2][3],22], the plasticity of EGCs is instead primarily evidenced under pathological circumstances, such as intestinal inflammation or infection, which trigger reactive gliosis. In addition to transient changes in the expression of glial markers (e.g., GFAP, S100β) [98][4], reactive EGCs can be characterized by changes in morphology (e.g., increased length and thickness of glial processes) [99][5], secretion of pro-inflammatory mediators (e.g., IL-1B, IL-6, NO) [100[6][7][8],101,102], immune competence (e.g., T lymphocyte activation via surface expression of MHC-II) [103][9], proliferative activity [104][10] or pro-apoptotic potential [105][11].
Depending on context, these changes are believed to have either detrimental effects by exacerbating pathological inflammatory processes or beneficial effects by neutralizing inflammation and promoting repair [22][3]. Accordingly, a s indicated in Section 5, some of these aspects of reactive enteric gliosis are currently considered potential therapeutic targets for several gastrointestinal diseases. However, optimizing such approaches will require a better understanding of how the different EGC subtypes respond to gliosis triggers. As such responses are likely variable as a function of EGC subtypes, this knowledge might pave the way to more precise interventions restricted to single EGC subtypes.

1.2. EGCs’ Multipotency

In addition to their extensive phenotypic plasticity, a subset of EGCs have the remarkable capacity to self-renew and differentiate into enteric neurons. Current knowledge suggests that this subset of EGCs with stem cell-like properties corresponds to what was initially reported to be a population of postnatal/adult ENS stem cells in mice [106,107,108][12][13][14] and humans [109,110,111][15][16][17]. As outlined in Table 1, the stem cell-like properties of EGCs vary as a function of experimental conditions in mice, being virtually undetectable under steady-state conditions in vivo. Yet, proliferation and neuronal differentiation of adult EGCs do exist during homeostasis in zebrafish [112][18], suggesting that these properties were somehow attenuated during vertebrate evolution. The stem cell-like properties of mammalian EGCs are nonetheless especially obvious in vitro, where EGCs sorted from adult bowels can not only be differentiated into neurons and glia but also into myofibroblasts [113][19]—as also noted in the early reports of postnatal/adult ENS stem cells [106,107,108,109][12][13][14][15]. Whether postnatal EGCs have this capacity to generate myofibroblasts in vivo is currently unknown. If it exists, this differentiation potential will probably require special circumstances to be revealed. Smooth muscle injury would most likely be a prerequisite in this case, just like ENS injury appears required to awake the self-renewing and neurogenic potential of EGCs in mice [114,115,116][20][21][22].
Table 1. Multipotency analyses of mature EGCs in mice.
References Experimental Condition Relevant Results
Joseph et al., 2011 [113][19] CD49b+ EGCs sorted from the small intestine (muscles and myenteric plexus) of adult WT mice. Sorted CD49b+ cells express glial markers (GFAP, SOX10, S100β, p75, and Nestin) and can be cultured as self-renewing neurospheres that differentiate in peripherin+ neurons, GFAP+ EGCs and α-SMA+ myofibroblasts.
BrdU incorporation assays in the small intestine of adult WT mice (and rats) housed in normal conditions or exposed to various potential triggers of neurogenesis (e.g., DSS-induced inflammation, BAC-induced focal aganglionosis). Basal enteric gliogenesis is detectable under steady-state condition, becoming markedly increased after certain types of injury (up to 90% of S100β+ were also BrdU+ in BAC-ablated regions). No evidence of neurogenesis, with exception of a single rat (out of 85 rodents in total) in which 6.1% of HuC/D+ myenteric neurons did incorporate BrdU in BAC-ablated region.
Cell lineage tracing in the small intestine of adult GFAP-Cre;R26R-YFP or GFAP-CreERT2;R26R-YFP mice, exposed to BAC treatment or not. With the constitutive Cre driver line, 6–7% of HuC/D+ myenteric neurons were also YFP+ in both control and BAC-treated mice. This most likely reflects an early fetal/neonatal contribution from a GFAP+ progenitor, which was no longer detectable when the tamoxifen-inducible Cre driver was activated in adults (<0.1% of HuC/D+ also YFP+ in this case).
Laranjeira et al., 2011 [116][22] Cultures of enzymatically dissociated small intestine (muscles and myenteric plexus) from tamoxifen-treated adult Sox10-iCreERT2;R26R-YFP or hGFAP-CreERT2;R26R-YFP mice. YFP+ cells generate bipotential SOX10+ PHOX2B+ ASCL1+ ENS progenitors that can be cultured as self-renewing neurospheres, and can be differentiated in GFAP+ EGCs and multiple neuronal subtypes (nNOS+, VIP+, or NPY+).
Cell lineage tracing studies in the small intestine of adult Sox10-iCreERT2;R26R-YFP mice, exposed to BAC treatment or not. YFP+ HuC/D+ myenteric neurons are not detected following tamoxifen treatment under steady-state conditions but are readily detected upon BAC-mediated ENS ablation.
Belkind-Gerson et al., 2013 [117][23] Neurospheres prepared from enzymatically dissociated colon (mucosa and submucosal plexus vs. muscles and myenteric plexus) of Nestin-GFP mice. GFP+ cells co-express glial markers (S100β, GFAP) in vivo, and generate neurospheres containing TuJ1+ neurons and S100β+ EGCs that both co-express GFP in culture.
Belkind-Gerson et al., 2015 [115][21] Pseudo cell lineage tracing studies in colon of Sox2-GFP and Nestin-GFP mice, exposed to DSS treatment or not. In absence of DSS, GFP expression is virtually undetectable in HuC/D+ myenteric neurons but becomes detectable 48 h after DSS treatment (8% of neurons in Sox2-GFP vs. 1.8% in Nestin-GFP mice).
Culture of CD49+ EGCs sorted from small intestine and colon (muscles and myenteric plexus) of adult mice, in absence or presence of a serotonin receptor antagonist Sorted CD49b+ EGCs generate TuJ1+ neurons, GFAP+ EGCs and TuJ1+ GFAP+ neuroglial cells in culture. The serotonin receptor antagonist increases the proportion of these neuroglial cells at the expense of neurons.
Transplantation of neurospheres derived from CD49b+ EGCs in explants of aneural embryonic chick hindgut Transplanted neurospheres generate TuJ1+ neurons and GFAP+ EGCs in both myenteric and submucosal plexus.
Belkind-Gerson et al., 2017 [114][20] Cell lineage tracing studies in colon of adult Sox2-CreERT2:R26R-YFP and Plp1-CreERT2:R26R-tdTomato mice, exposed to DSS treatment or not. DSS treatment increases the proportion of HuC/D+ myenteric and submucosal neurons co-expressing either of the fluorescent reporters in tamoxifen-induced mice.
Neurospheres prepared from enzymatically dissociated colon (full thickness) of adult tamoxifen-treated Plp1-CreERT2;R26R-tdTomato mice. tdTomato is expressed in neurons (either TuJ1+, HuC/D+, or PGP9.5+), EGCs (either SOX2+ or S100β+), and neuroglial cells co-expressing neuronal and glial markers.
Guyer et al., 2023 [30][24] Neurospheres prepared from enzymatically dissociated small intestine (muscles and myenteric plexus) of adult Plp1-GFP;Actl6b-Cre;R26R-tdTomato dual reporter mice. GFP+ EGCs sorted from neurospheres generate new tdTomato+ neurons in culture.
Sorted tdTomato-negative cells from small intestine (muscles and myenteric plexus) of adult Actl6b-Cre;R26R-tdTomato mice. Neurospheres derived from sorted tdTomato-negative cells generate new tdTomato+ neurons in culture.
Abbreviations: BAC, benzalkonium chloride; BrdU, bromodeoxyuridine; DSS, dextran sodium sulfate.
Further research is clearly necessary to fully understand both the nature and the regulatory mechanisms of EGCs’ stem cell-like properties in mammals. One especially important question to address is whether the self-renewal and multipotency of EGCs seen at the population level are combined in a specific EGC subtype or are instead divided in different EGC subtypes. Comparison of thymidine analog incorporation assays and cell lineage tracing studies suggest that neuronal differentiation from EGCs mostly occurs independently of cell proliferation [113,114[19][20][22],116], but both types of analyses will need to be combined to clearly establish the extent of such trans-differentiation capacity. In connection with this, are EGC-derived neurons exclusively made from the neurogenic EGC subtypes recently identified by scRNA-seq [30][24]? Do each of the two neurogenic EGC subtypes identified in this study generate mutually exclusive neuron subtypes? Similar questions specifically arise for the self-renewal of EGCs. Is it an intrinsic property of all topo-morphological subtypes of EGCs? Responses to all these questions will be required to take full advantage of EGCs’ multipotency for therapeutic purposes.

2. Taking Advantage of EGCs’ Plasticity and Multipotency for Therapeutic Purposes

2.1. Control of Inflammation and Infection in the Gastrointestinal Tract

As mentioned in the previous section, reactive EGCs are involved in the pathogenesis of various gastrointestinal disorders [22][3]. In the case of IBD (inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease), reactive EGCs primarily adopt a pro-inflammatory phenotype that exacerbates both innate and adaptative immune responses [21][25]. Similar observations have also been made in the context of IBS (irritable bowel syndrome) [118,119][26][27] and POI (postoperative ileus) [120][28]. Although there are no specific drugs/products that specifically target EGCs, several studies have nonetheless successfully modulated the detrimental effects of enteric gliosis for therapeutic purposes [22,121][3][29]. For example, Pentamidine, a broad-spectrum anti-infective small molecule that targets and inhibits S100β, can prevent 5-Fluorouracil-induced intestinal mucositis and associated enteric neurotoxicity by decreasing S100β secretion from reactive EGCs, thereby attenuating downstream RAGE/NF-κB signaling [122][30]. Interestingly, not only conventional drugs but also nutraceutical products have shown promising effects in modulating the pathological effects of reactive EGCs [121][29]. For instance, the cannabinoid-related PEA (palmitoylethanolamide, found in soybeans and peanuts) was reported to exert an anti-inflammatory effect in the context of ulcerative colitis by targeting and activating PPARα which then inhibits S100β production/secretion from reactive EGCs [123][31]. Of note, PEA also proved useful in the case of HIV-1 Tat-induced diarrhea via the same PPARα-dependent mechanism in reactive EGCs [124][32]. While most therapeutic strategies in this area focus on mitigating the deleterious effects of reactive EGCs, it should not be forgotten that these cells may also have beneficial effects that might be taken advantage of. One especially appealing possibility would be to control the secretion of GDNF, which was found to be turned on in reactive EGCs in the context of Crohn’s disease [125][33], and whose beneficial effects on restoring epithelial barrier integrity in this same pathological context are well known [126,127][34][35].

2.2. Repair and Regeneration of the ENS

The discovery of postnatal/adult ENS stem cells [106,107,108,109,110,111][12][13][14][15][16][17] has sparked great interest for the development of cell transplantation-based therapies aimed at regenerating the damaged/missing ENS. WRsearche rs now assume that this stem/progenitor cell population is mostly composed of intrinsic EGCs, but at least a minor contribution from extrinsic Schwann cells is also likely. Indeed, extrinsic Schwann cells are closely associated with intestinal tissues and are often labeled with the same transgenic markers (driven by Plp1, Nestin or Sox10 regulatory sequences) used to label EGCs, and thus are hard to be excluded from gastrointestinal cell preparations. Moreover, reminiscent of the normal capacity of SCPs to form enteric neurons during late ENS development [46][36], Schwann cells from adult peripheral nerves can be grown as neurospheres and differentiated into neurons both in culture and when transplanted in the mouse gastrointestinal tract in vivo [128][37]. Mouse models of Hirschsprung disease have been the preferred tools for testing and developing cell transplantation-based therapies [128[37][38][39][40][41][42][43],129,130,131,132,133,134], although diseases with less severe phenotypes (e.g., oesophageal achalasia, gastroparesis) are now increasingly recognized as likely being more amenable to therapy in a real-world setting [135][44]. Hirschsprung disease is characterized by the complete lack of ENS ganglia over varying lengths of the rectum and distal colon, due to incomplete colonization by vagal NCC-derived ENS progenitors [33,136][45][46]. Yet, the so-called aganglionic segment is naturally enriched in Schwann cells owing to the overabundance of extrinsic nerves in this context [137][47]. This has important practical implications for highly desirable autologous cell-based therapies, explaining why not only the ENS-containing region [132][41], but also the ENS-devoid region [138[48][49],139], can be a source of ENS stem/progenitor cells likely enriched in EGCs and Schwann cells, respectively. However, it is currently unclear if both sources can generate the same complement of enteric neuron subtypes after ex vivo expansion and in vivo transplantation. SCP-derived enteric neurons are normally strongly biased towards an excitatory CALR+ phenotype, with only minimal contribution to the inhibitory NOS1+ pool [46][36]. Although cell culture can reprogram the cell differentiation potential, the extent of derivatives made from EGC- and Schwann cell-derived ENS stem/progenitor cells might nonetheless remain skewed somehow. The same question also applies to the diversity of EGC subtypes that can be engendered from each source of ENS stem/progenitor cells. One possibility for maximizing neuronal and glial diversification—and, hence, functional recovery of the reconstituted ENS—would be to co-transplant ENS stem/progenitor cells of different origins, as recently experimented for vagal and sacral NCC-derived ENS progenitors differentiated from human pluripotent stem cells [134][43]. That being said, in situ stimulation of tissue-resident ENS stem/progenitor cells appears as a much simpler approach to address this issue, and GDNF proved to be a potent trigger in this context [140,141][50][51]. Indeed, rectal administration of GDNF over a relatively short period of time after birth (five days) induced a new functional ENS in the otherwise aganglionic colon of three genetically distinct mouse models of Hirschsprung disease (Piebald-Lethal [142][52], Holstein [143][53] and TashT [144][54]). This treatment stimulated neurogenesis and gliogenesis in both aganglionic and hypoganglionic segments [140[50][51],141], generating several neuronal subtypes in the aganglionic zone while also correcting the cholinergic vs. nitrergic neuronal imbalance normally found in the upstream hypoganglionic zone [141,145][51][55]. Intriguingly, genetic cell lineage tracing studies using the Schwann cell-specific Cre driver Dhh-Cre revealed that only about a third of GDNF-induced neurons are derived from this lineage in the aganglionic segment. Moreover, combined EdU incorporation assays showed that the majority of GDNF-induced neurons were not derived from a dividing precursor. Other data suggest that sacral NCC-derived EGCs might also be present in the aganglionic segment [141][51], but their contribution to the regenerative process, if any, is currently unknown. Like for cell transplantation-based therapies, it also remains to be known if Schwann cell- and EGC-derived ENS stem/progenitor cells generate their own set of neuronal and glial subtypes. Addressing these questions in the context of Hirschsprung disease will also be important for improving ourthe general knowledge of ENS stem/progenitor cells.

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