Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent
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 p...
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doaj-fdf3e528943d4efd961a78c7af8af8702021-02-15T00:01:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01221887188710.3390/ijms22041887Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-DependentMichael Meir0Felix Kannapin1Markus Diefenbacher2Yalda Ghoreishi3Catherine Kollmann4Sven Flemming5Christoph-Thomas Germer6Jens Waschke7Patrick Leven8Reiner Schneider9Sven Wehner10Natalie Burkard11Nicolas Schlegel12Department of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of Biochemistry and Molecular Biochemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of Anatomy and Cell Biology University of Munich, Pettenkoferstrasse 11, 80336 Munich, GermanyDepartment of Surgery, University Clinic Bonn, Venusberg-Campus 1, 53105 Bonn, GermanyDepartment of Surgery, University Clinic Bonn, Venusberg-Campus 1, 53105 Bonn, GermanyDepartment of Surgery, University Clinic Bonn, Venusberg-Campus 1, 53105 Bonn, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyDepartment of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, GermanyEnteric 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 GFAP<sup>cre</sup> x Ai14<sup>floxed</sup> 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.https://www.mdpi.com/1422-0067/22/4/1887enteric glial cellsneurotrophic factorsintestinal epithelial barrierGDNF5RET6inflammatory bowel disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael Meir Felix Kannapin Markus Diefenbacher Yalda Ghoreishi Catherine Kollmann Sven Flemming Christoph-Thomas Germer Jens Waschke Patrick Leven Reiner Schneider Sven Wehner Natalie Burkard Nicolas Schlegel |
spellingShingle |
Michael Meir Felix Kannapin Markus Diefenbacher Yalda Ghoreishi Catherine Kollmann Sven Flemming Christoph-Thomas Germer Jens Waschke Patrick Leven Reiner Schneider Sven Wehner Natalie Burkard Nicolas Schlegel Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent International Journal of Molecular Sciences enteric glial cells neurotrophic factors intestinal epithelial barrier GDNF5 RET6 inflammatory bowel disease |
author_facet |
Michael Meir Felix Kannapin Markus Diefenbacher Yalda Ghoreishi Catherine Kollmann Sven Flemming Christoph-Thomas Germer Jens Waschke Patrick Leven Reiner Schneider Sven Wehner Natalie Burkard Nicolas Schlegel |
author_sort |
Michael Meir |
title |
Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent |
title_short |
Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent |
title_full |
Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent |
title_fullStr |
Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent |
title_full_unstemmed |
Intestinal Epithelial Barrier Maturation by Enteric Glial Cells is GDNF-Dependent |
title_sort |
intestinal epithelial barrier maturation by enteric glial cells is gdnf-dependent |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
description |
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 GFAP<sup>cre</sup> x Ai14<sup>floxed</sup> 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. |
topic |
enteric glial cells neurotrophic factors intestinal epithelial barrier GDNF5 RET6 inflammatory bowel disease |
url |
https://www.mdpi.com/1422-0067/22/4/1887 |
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