1. Academic Validation
  2. Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent

Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent

  • Int J Mol Sci. 2021 Feb 14;22(4):1887. doi: 10.3390/ijms22041887.
Michael Meir 1 Felix Kannapin 1 Markus Diefenbacher 2 Yalda Ghoreishi 1 Catherine Kollmann 1 Sven Flemming 1 Christoph-Thomas Germer 1 Jens Waschke 3 Patrick Leven 4 Reiner Schneider 4 Sven Wehner 4 Natalie Burkard 1 Nicolas Schlegel 1
Affiliations

Affiliations

  • 1 Department of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, Germany.
  • 2 Department of Biochemistry and Molecular Biochemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
  • 3 Department of Anatomy and Cell Biology University of Munich, Pettenkoferstrasse 11, 80336 Munich, Germany.
  • 4 Department of Surgery, University Clinic Bonn, Venusberg-Campus 1, 53105 Bonn, Germany.
Abstract

Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAPcre x Ai14floxed mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.

Keywords

GDNF5; RET6; enteric glial cells; enteric nervous system; gut barrier; inflammatory bowel disease; intercellular junctions; intestinal epithelial barrier; neurotrophic factors.

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