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

Meir, Michael; Kannapin, Felix; Diefenbacher, Markus E.; Ghoreishi, Yalda; Kollmann, Cathérine; Flemming, Sven; Germer, Christoph‐Thomas; Waschke, Jens; Leven, Patrick; Schneider, Reiner; Wehner, Sven; Burkard, Natalie; Schlegel, Nicolas

doi:10.3390/ijms22041887

Cited by 38 publications

(30 citation statements)

References 45 publications

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“… 57 Even if it is so, the underlying mechanisms of how EGCs may influence epithelial cells and the maintenance of intestinal epithelial barrier function remain undefined. 58 Through our results, we can speculate that the α-syn positive EECs may act as a possible chemosensory link between mucosal EGCs and the intestinal lumen, inducing changes in the intestinal homeostasis at the base of the gut disorders. In the end, our findings show three protagonists of the intestinal changes, anatomically localized in strategic positions: EECs, EGCs and ENS.…”

Section: Discussionmentioning

confidence: 58%

Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system

et al. 2021

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Alpha-synuclein (α-syn) is a presynaptic neuronal protein and its structural alterations play an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease (PD). It has been originally described in the brain and aggregated α-syn has also been found in the peripheral nerves including the enteric nervous system (ENS) of PD patients. ENS is a network of neurons and glia found in the gut wall which controls gastrointestinal function independently from the central nervous system. Moreover, two types of epithelial cells are crucial in the creation of an interface between the lumen and the ENS: they are the tuft cells and the enteroendocrine cells (EECs). In addition, the abundant enteric glial cells (EGCs) in the intestinal mucosa play a key role in controlling the intestinal epithelial barrier. Our aim was to localize and characterize the presence of α-syn in the normal human jejunal wall. Surgical specimens of proximal jejunum were collected from patients submitted to pancreaticoduodenectomy and intestinal sections underwent immunohistochemical procedure. Alpha-syn has been found both at the level of ENS and the epithelial cells. To characterize α-syn immunoreactive epithelial cells, we used markers such as choline acetyltransferase (ChAT), useful for the identification of tuft cells. Then we evaluated the co-presence of α-syn with serotonin (5-HT), expressed in EECs. Finally, we used the low-affinity nerve growth factor receptor (p75NTR), to detect peripheral EGCs. The presence of α-syn has been demonstrated in EECs, but not in the tuft cells. Additionally, p75NTR has been highlighted in EECs of the mucosal layer and co-localized with α-syn in EECs but not with ChAT-positive cells. These findings suggest that α-syn could play a possible role in synaptic transmission of the ENS and may contribute to maintain the integrity of the epithelial barrier of the small intestine through EECs.

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Section: Discussionmentioning

confidence: 58%

Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system

et al. 2021

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“…Notably, in embryonic gut development GDNF is expressed by EMCs and not ENCDCs. Nevertheless, GDNF is expressed postnatally by enteric glial cells, which appears to have important effects on epithelial barrier maintenance 49 . This highlights a degree of disparity between embryonic ENSCs and those isolated and cultured from postnatal intestine which requires further elucidation.…”

Section: Discussionmentioning

confidence: 99%

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Stavely

Bhave

et al. 2021

Stem Cells

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Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb −/− mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb +/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb −/− mice generated functional neurons with similar calcium responses to Ednrb +/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb −/− recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

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“…EGCs are the predominant cellular source of glial cell line-derived neurotrophic factor (GDNF) in the gut (Meir et al, 2021 ). GDNF could strengthen the barrier integrity by preventing the apoptosis of intestinal epithelial cells (Savidge et al, 2007 ; Zhang et al, 2010 ).…”

Section: Immune Functions Of Egcsmentioning

confidence: 99%

“…Third, EGCs might present disease-related antigens to modulate the gut adaptive immunity (Geboes et al, 1992 ). Finally, EGCs are able to crosstalk indirectly or directly with the epithelial layer and influence the barrier integrity (Li et al, 2016 ; Meir et al, 2021 ). We will focus on the available evidence supporting the roles of EGCs in several gut diseases, i.e., inflammatory bowel disease, celiac disease, and autoimmune enteropathy ( Figure 2 ).…”

Section: Egcs In Immunological Disordersmentioning

confidence: 99%

Enteric Glial Cells in Immunological Disorders of the Gut

Liu

Yang

2022

Front. Cell. Neurosci.

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Enteric glial cells (EGCs) are one of the major cell types of neural crest lineage distributed in the gastrointestinal tract. EGCs represent an integral part of the enteric nervous system (ENS) and significantly outnumber ENS neurons. Studies have suggested that EGCs would exert essential roles in supporting the survival and functions of the ENS neurons. Notably, recent evidence has begun to reveal that EGCs could possess multiple immune functions and thereby may participate in the immune homeostasis of the gut. In this review article, we will summarize the current evidence supporting the potential involvement of EGCs in several important immunological disorders, including inflammatory bowel disease, celiac disease, and autoimmune enteropathy. Further, we highlight critical questions on the immunological aspects of EGCs that warrant future research attention.

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

Cited by 38 publications

References 45 publications

Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system

Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells

Enteric Glial Cells in Immunological Disorders of the Gut

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