cells Review Neuron–Glia Interaction in the Developing and Adult Enteric Nervous System Verena Pawolski and Mirko H. H. Schmidt * Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany; [email protected] * Correspondence: [email protected] Abstract: The enteric nervous system (ENS) constitutes the largest part of the peripheral nervous system. In recent years, ENS development and its neurogenetic capacity in homeostasis and allostasis have gained increasing attention. Developmentally, the neural precursors of the ENS are mainly derived from vagal and sacral neural crest cell portions. Furthermore, Schwann cell precursors, as well as endodermal pancreatic progenitors, participate in ENS formation. Neural precursors enherite three subpopulations: a bipotent neuron-glia, a neuronal-fated and a glial-fated subpopulation. Typically, enteric neural precursors migrate along the entire bowel to the anal end, chemoattracted by glial cell-derived neurotrophic factor (GDNF) and endothelin 3 (EDN3) molecules. During migration, a fraction undergoes differentiation into neurons and glial cells. Differentiation is regulated by bone morphogenetic proteins (BMP), Hedgehog and Notch signalling. The fully formed adult ENS may react to injury and damage with neurogenesis and gliogenesis. Nevertheless, the origin of differentiating cells is currently under debate. Putative candidates are an embryonic-like enteric neural progenitor population, Schwann cell precursors and transdifferentiating glial cells. These cells can be isolated and propagated in culture as adult ENS progenitors and may be used for cell transplantation therapies for treating enteric aganglionosis in Chagas and Hirschsprung’s diseases. Keywords: neuron-glia interaction; neural crest cells; enteric nervous system; gastrointestinal system; gut; GDNF; EDN3; Notch; BMP; hedgehog Citation: Pawolski, V.; Schmidt, M.H.H. Neuron–Glia Interaction in the Developing and Adult Enteric Nervous System. Cells 2021, 10, 47. 1. Introduction https://doi.org/10.3390/cells10010047 The enteric nervous system (ENS) developed in evolutionary terms independently and earlier than the central nervous system (CNS) [1]. With its 200–600 million neurons in Received: 14 November 2020 humans, the ENS contains as many neurons as the neural tube and is, therefore, considered Accepted: 29 December 2020 the largest part of the peripheral nervous system (PNS) [2]. The ENS is a complex, au- Published: 31 December 2020 tonomous nervous system which coordinates all bowel functions [3]. It is connected with the CNS via the sympathetic, parasympathetic and sensory system. Most prominent is its Publisher’s Note: MDPI stays neu- connection to the brain by the vagus nerve for the communication of content composition tral with regard to jurisdictional clai- and hunger [4,5]. In this way, stimulation of the CNS by the gut influences hippocampal ms in published maps and institutio- nal affiliations. learning and memory and regulates motivation and emotions [6,7]. A key component are the gut bacteria. The gut microbiome heavily interacts with the ENS and influences gut physiology [8,9]. The ENS modulates immune cells within the gut wall, which in- fluence the microbiome and the formation of cancer, abdominal pain and neurological Copyright: © 2020 by the authors. Li- disorders such as Parkinson’s disease [10–16]. The diversity in neuronal and glial subtypes, censee MDPI, Basel, Switzerland. as well as the diversity of neurotransmitters, is comparably rich as in the CNS [17]. Not This article is an open access article all aspects of neuron-glia interaction are fully understood yet, but it is evident that in distributed under the terms and con- both systems, physiological neural development and function depend on their functional ditions of the Creative Commons At- interaction [18,19]. In the CNS, neurons and glial cells influence each other during matura- tribution (CC BY) license (https:// tion and function. Glial cells promote neurogenesis, coordinate neuronal migration, axon creativecommons.org/licenses/by/ growth, the formation of synapses and are involved in neural circuit functions [19]. Glia 4.0/). Cells 2021, 10, 47. https://doi.org/10.3390/cells10010047 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 21 Cells 2021, 10, 47 2 of 20 axon growth, the formation of synapses and are involved in neural circuit functions [19]. areGlia themselves are themselves regulated regulated by neurons by neurons which which modulate modulate their their transcriptome transcriptome and numbers,and num- probablybers, probably to shape to theshape neural the networksneural networks in the brain in the [20 brain]. In the [20]. ENS, In the glial ENS, cells glial are similarly cells are crucialsimilarly for crucial neuroprotection, for neuroprotection, neural maturation, neural maturation, synapses formation, synapses asformation, well as the as releasewell as andthe release degradation and degradation of neurotransmitters of neurotransmitters [18,21,22]. [18,21,22]. TheThe multipotentmultipotent stem stem cells cells of of the the CNS CNS are are the the radial radial glial glial cells, cells, which which may may differentiate differen- intotiate glia into and glia neurons and neurons [23]. In [23]. the ENS,In the compatible ENS, compatible functions functions are fulfilled are fulfilled by enteric by neuralenteric crest-derivedneural crest-derived cells (ENCC), cells (ENCC), which represent which repr theesent enteric the neural enteric progenitor neural progenitor population popula- [24]. Enteriction [24]. neurons Enteric are neurons distributed are distributed along the digestive along the tract digestive in two tract different in two plexuses different of plexuses ganglia: theof ganglia: submucosal the submucosal plexus, and pl theexus, myenteric and the myenteric plexus (Figure plexus1a). (Figure The submucosal1a). The submucosal plexus consistsplexus consists of a concentric of a concentric arrangement arrangement of enteric of enteric ganglia ganglia in the submucosa,in the submucosa, the tissue the layertissue adjacentlayer adjacent to the luminalto the luminal epithelium. epithelium. The myenteric The myenteric plexus isplexus dispersed is dispersed between between the circular the andcircular longitudinal and longitudinal smooth muscle smooth layers muscle of thelayers enteric of the canal. enteric Several canal. signalling Several pathwayssignalling arepathways associated are withassociated plexus with patterning plexus (Sonic pattern hedgehoging (Sonic (SHH), hedgehog bone morphogenic (SHH), bone proteinmorpho- 2 andgenic 4 (BMP2protein and 2 and 4) Netrin),4 (BMP2and4) neural Netrin), differentiation neural (Neurotrophin-3,differentiation (Neurotrophin-3, BMP2, 4), gliogenesis BMP2, (Neuregulin4), gliogenesis 1 (GGF2), (Neuregulin Notch) 1 (GGF2), and axonal Notch) growth and (Semaphorin axonal growth 3A, (Semaphorin Neuturin) [25 3A,]. How- Neu- ever,turin) on [25]. what However, stage of differentiationon what stage theseof diff moleculeserentiation act these and howmolecules they interact act and with how each they otherinteract remains with each mostly other unknown. remains mostly unknown. FigureFigure 1.1.Enteric Enteric nervousnervous system system (ENS) (ENS) precursors precursors colonize colonize the the gut gut in in two two waves. waves. (a )(a Enteric) Enteric ganglia gan- formglia form the myenteric the myenteric plexus plexus (MP) (M betweenP) between the circular the circular (CM) and(CM) longitudinal and longitudinal muscle muscle (LM) layers(LM) lay- and ers and the submucosal plexus (SMP) in the mucosa. (b) The majority of neural precursors are the submucosal plexus (SMP) in the mucosa. (b) The majority of neural precursors are derived from derived from the vagal neural crest, adjacent to somites 1 to 7 (orange). They migrate along the the vagal neural crest, adjacent to somites 1 to 7 (orange). They migrate along the bowel in an oral to bowel in an oral to anal direction. A second group originates from sacral neural crest cells (in mice analbehind direction. somite A24), second forms group the pelvic originates ganglia from (pg) sacral and migrates neural crest in an cells anal (in to miceoral direction behind somite (red). 24), formsFurther the enteric pelvic neural ganglia precursors (pg) and migratesare descendants in an anal of Schwann to oral direction cell precurso (red).rs Further (SCP, green) enteric or neural pan- precursorscreatic progenitors are descendants (blue). ( ofc) SchwannNeural-fated cell enteric precursors neural (SCP, crest- green)derived or pancreatic cells (ENCCs) progenitors (N) differen- (blue). (ctiate) Neural-fated in the myenteric enteric region neural (gre crest-derivedy). In parallel, cells neuron-glia (ENCCs) (N) bipo differentiatetent (N-G) inand the glial-fated myenteric ENCCs region (grey).(G) migrate In parallel, into the neuron-glia mucosal area bipotent (yellow) (N-G) and and differentiate glial-fated further ENCCs into (G) neurons migrate and into glial the mucosal cells.; h areaheart; (yellow) ld liver and diverticulum, differentiate pd further pancreatic into neuronsdiverticulum, and glial c caecum. cells.; h heart; ld liver diverticulum, pd pancreatic diverticulum, c caecum. 2. Neurons and Glia during Enteric Nervous System (ENS) Formation 2.2.1. Neurons Neural Precursors and Glia duringArise from Enteric Multiple Nervous Sources System (ENS) Formation