title: 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.
authors.affiliation: INSERM U, Nantes, France.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Van Landeghem
authors.forename: Julien
authors.initials: J
authors.lastname: Chevalier
authors.forename: Maxime M
authors.initials: MM
authors.lastname: Mahé
authors.forename: Thilo
authors.initials: T
authors.lastname: Wedel
authors.forename: Petri
authors.initials: P
authors.lastname: Urvil
authors.forename: Pascal
authors.initials: P
authors.lastname: Derkinderen
authors.forename: Tor
authors.initials: T
authors.lastname: Savidge
authors.forename: Michel
authors.initials: M
authors.lastname: Neunlist
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018938:Caco-2 Cells; D048430:Cell Shape; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D016264:Dextran Sulfate; D004008:Diclofenac; D004195:Disease Models, Animal; D004751:Enteritis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology; D019899:Paracrine Communication; D010437:Peptic Ulcer / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014945:Wound Healing
chemical_list: D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; C042652:epidermal growth factor precursor; C528900:glial fibrillary astrocytic protein, mouse; D004008:Diclofenac; D004815:Epidermal Growth Factor; D016264:Dextran Sulfate; D013937:Thymidine Kinase; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse