Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system

TLDR

Enteric glial cells are essential for autonomic control of gastrointestinal homeostasis, yet it remains unclear whether distinct subtypes with specialized phenotypes exist. The authors employed Mosaic Analysis with Double Markers and inducible lineage tracing to map morphology and dynamic marker expression of myenteric plexus glia, complemented by Ca²⁺ imaging of individual cells. Four morphologically distinct enteric glial subpopulations were identified, with most myenteric glia co‑expressing GFAP, S100β, and Sox10, while up to 80 % of glia outside ganglia lacked these markers; lineage tracing indicated that marker combinations reflect dynamic gene regulation, and functional assays revealed that three myenteric subtypes differ in ATP‑evoked responses, demonstrating extensive heterogeneity and phenotypic plasticity. Published in GLIA 2015;63:229–241.

Abstract

Enteric glial cells are vital for the autonomic control of gastrointestinal homeostasis by the enteric nervous system. Several different functions have been assigned to enteric glial cells but whether these are performed by specialized subtypes with a distinctive phenotype and function remains elusive. We used Mosaic Analysis with Double Markers and inducible lineage tracing to characterize the morphology and dynamic molecular marker expression of enteric GLIA in the myenteric plexus. Functional analysis in individually identified enteric glia was performed by Ca 2+ imaging. Our experiments have identified four morphologically distinct subpopulations of enteric glia in the gastrointestinal tract of adult mice. Marker expression analysis showed that the majority of glia in the myenteric plexus co‐express glial fibrillary acidic protein (GFAP), S100β, and Sox10. However, a considerable fraction (up to 80%) of glia outside the myenteric ganglia, did not label for these markers. Lineage tracing experiments suggest that these alternative combinations of markers reflect dynamic gene regulation rather than lineage restrictions. At the functional level, the three myenteric glia subtypes can be distinguished by their differential response to adenosine triphosphate. Together, our studies reveal extensive heterogeneity and phenotypic plasticity of enteric glial cells and set a framework for further investigations aimed at deciphering their role in digestive function and disease. GLIA 2015;63:229–241