Harnessing the Power of Enteric Glial Cells' Plasticity and Multipotency for Advancing Regenerative Medicine

Abstract

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. In this review, we aim to provide an updated overview of the current knowledge on this subject, while also identifying key questions that necessitate future exploration.

Keywords: Hirschsprung disease; Schwann cells; diversity; enteric glial cells; inflammatory bowel diseases; multipotency; neural crest cells; plasticity; regenerative medicine.

Figure 1

Tissue distribution of the 4 topo-morphological subtypes of EGCs in murine duodenum at P20. (A,B) Double immunofluorescence staining of S100β-positive EGCs and βIII-Tubulin-positive enteric neurons and nerve fibers at the level of myenteric ganglia (A) and circular muscle layer (B). As indicated by arrows, EGCs Type 1 are located in myenteric ganglia, Type II in thick interganglionic nerve fibers, while Type III and Type IV are both associated with thin extraganglionic neuronal fibers. Scale bar, 50 µm.

Figure 2

Distribution of SLC18A2 protein in the myenteric plexus of WT mice at P10. Triple immunofluorescence staining shows that SLC18A2 predominantly labels SOX10-positive EGCs Type 1, but also SOX10-negative EGCs Type II and Type III (see arrows in merge panel). βIII-Tubulin labels enteric neurons and nerve fibers. Scale bar, 100 µm.