Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF

Abstract

Wound healing of the gastrointestinal mucosa is essential for the maintenance of gut homeostasis and integrity. Enteric glial cells play a major role in regulating intestinal barrier function, but their role in mucosal barrier repair remains unknown. The impact of conditional ablation of enteric glia on dextran sodium sulfate (DSS)-induced mucosal damage and on healing of diclofenac-induced mucosal ulcerations was evaluated in vivo in GFAP-HSVtk transgenic mice. A mechanically induced model of intestinal wound healing was developed to study glial-induced epithelial restitution. Glial-epithelial signaling mechanisms were analyzed by using pharmacological inhibitors, neutralizing antibodies, and genetically engineered intestinal epithelial cells. Enteric glial cells were shown to be abundant in the gut mucosa, where they associate closely with intestinal epithelial cells as a distinct cell population from myofibroblasts. Conditional ablation of enteric glia worsened mucosal damage after DSS treatment and significantly delayed mucosal wound healing following diclofenac-induced small intestinal enteropathy in transgenic mice. Enteric glial cells enhanced epithelial restitution and cell spreading in vitro. These enhanced repair processes were reproduced by use of glial-conditioned media, and soluble proEGF was identified as a secreted glial mediator leading to consecutive activation of epidermal growth factor receptor and focal adhesion kinase signaling pathways in intestinal epithelial cells. Our study shows that enteric glia represent a functionally important cellular component of the intestinal epithelial barrier microenvironment and that the disruption of this cellular network attenuates the mucosal healing process.

Human and Murine Tissue-Engineered Colon Exhibit Diverse Neuronal Subtypes and Can Be Populated by Enteric Nervous System Progenitor Cells When Donor Colon Is Aganglionic

“…42 Further regulation of mucosal proliferation and apoptosis in response to injury also occurs through enteric neuronal serotonin signaling, 43 calcitonin gene-related peptide, 44 enteric glial-derived s-nitrosoglutathione, 45 enteric glialderived neurotrophic factor, 46 and enteric glial-derived pro-EGF. 47 Several other genetic defects are implicated in HD, 38 and there is evidence that nongenetic causes, such as in utero exposures or vitamin A deficiency, 48 can result in HD-like phenotypes. 49 To assess this study's generalizability, future experiments will explore the potential of neurosphere supplementation in TEC derived from aganglionic colon of various etiologies.…”

Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum?

“…1c). The early effects are represented by a strong apoptosis of EGC, whereas the late effects, with the loss of a consistent number of EGC, might cause disruption of the network of this cell population, resulting in delay of mucosal healing [56] and, if the loss of EGC is massive and overcomes the reactive gliogenesis, most of their function is lost, with devastating effects on other cell populations (e.g., enteric neurons) and persistence of clinical consequences (abnormal motility and visceral perception).…”

Le système nerveux entérique et l’unité neuro-glio-épithéliale digestive

“…Le concept d'UNGE s'est développé récemment sur la base de données anatomiques montrant : -1) l'existence d'une importante innervation de la BEI composée d'axones et de cellules gliales, chaque villus étant innervé par 70-92 neurones sous-muqueux chez le cobaye (Song et al 1995) et -2) la proximité étroite entre les fibres nerveuses et les CEI, séparées uniquement par la lame basale dont l'épaisseur est de l'ordre du micromètre (Neunlist et al 2007 ;Van Landeghem et al 2011).…”

“…Outre leur rôle protecteur de la BEI, les CGE favorisent les processus de sa réparation après lésions, à la fois in vivo et in vitro, en favorisant l'étalement des CEI. Ces effets sont dus en partie à la production et à la libération du pro-epidermic growth factor (proEGF) par les CGE, conduisant à l'activation des récepteurs EGFR sur les CEI et la stimulation de ces récepteurs entraîne l'activation de la focal adhesion kinase ou FAK (Van Landeghem et al 2011). Enfin, les CGE jouent un rôle majeur dans le contrôle de la prolifération des CEI.…”