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

Patrick Leven,Christoph-Thomas Germer,Sven Wehner,Reiner Schneider,Natalie Burkard,Catherine Kollmann,Markus Diefenbacher,Sven Flemming,Nicolas Schlegel,Michael Meir,Felix Kannapin,Yalda Ghoreishi,Jens Waschke

doi:10.3390/ijms22041887

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.

Highlights

The intestinal epithelial barrier (IEB) plays an essential role in health and disease.This barrier is maintained by polarized and highly specialized cells, including enterocytes, goblet cells, Paneth cells, enteroendocrine cells and M-cells which line the whole gut lumen [1,2,3]
The present study extends our previous investigations on the role of neurotrophic factor Glial cell line-derived neurotrophic factor (GDNF) in the regulation of the intestinal epithelial barrier
We demonstrated that GDNF induces barrier maturation of intestinal epithelial cells and protects from loss of intestinal barrier function in inflammation that plays a key role in patients with

Summary

Introduction

The intestinal epithelial barrier (IEB) plays an essential role in health and disease. This barrier is maintained by polarized and highly specialized cells, including enterocytes, goblet cells, Paneth cells, enteroendocrine cells and M-cells which line the whole gut lumen [1,2,3]. It was shown that EGCs are reduced in the healthy, non-inflamed parts of the intestine of patients suffering from IBD prior to the onset of inflammation. This led to the assumption that EGCs might play an important early role in the pathogenesis of IBD [10,11]

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Conclusion