Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Meir, Michael; Burkard, Natalie; Ungewiß, Hanna; Diefenbacher, Markus E.; Flemming, Sven; Kannapin, Felix; Germer, Christoph‐Thomas; Schweinlin, Matthias; Metzger, Marco; Waschke, Jens; Schlegel, Nicolas

doi:10.1172/jci120261

Cited by 68 publications

(100 citation statements)

References 55 publications

(96 reference statements)

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“…41,42 Interestingly, GDNF is significantly reduced in patients with active inflammation in CD and UC. 30 Furthermore, there is evidence that a toxic or autoimmune ablation of enteric glial cells leads to breakdown of IEB function followed by a spontaneous jejuno-ileiits comparable to the phenotype seen in CD. 43,44 In line with this, enteric glial cells are reduced in healthy, non-inflamed parts of the intestine of patients suffering from IBD prior to the onset of inflammation.…”

Section: Cellular Component Of the Intestinal Barriermentioning

confidence: 99%

“…29 In a third cohort, Dsg2 was reduced in nine patients with CD and nine patients with CU, respectively, categorically indicating that the integrity of desmosomes is compromised in IBD patients, at least when the course of the disease is severe. 30 The resultant loss of Dsg2 impairs TJ integrity and function, which leads to disruption of barrier properties and increased susceptibility to infections similar to the situation in mice deficient for intestinal Dsg2. 29 Finally, in a cohort of 17 patients with CD loss of Dsg2 was also described, especially in severe inflammation.…”

Section: Levels and Desmosome Ultrastructure In Ibdmentioning

confidence: 99%

“…This picture was taken and modified from Gross et al 2018 after Copyright approval from Mucosal Immunology 29 More recently, it was shown that barrier dysfunction after TNF-α treatment was not only paralleled by activation of p38MAPK, but also associated with phosphorylation of cytokeratins 8 and 18 and by loss of Dsg2 in vitro and in vivo. 30 In this context, GDNF specifically targeted Dsg2 and thereby induced barrier maturation by preventing p38MAPK activation ( Figure 4). In DSS-colitis, inflammation-induced loss of Dsg2, p38MAPK and cytokeratin phosphorylation were attenuated by intraperitoneal GDNF treatment.…”

Section: Role Of Dsg2 In Experimental Colitis and As A Therapeuticmentioning

confidence: 99%

“…However, increasing evidence points towards a critical role for desmosomal adhesion and signalling in maintaining the intestinal barrier in both health and disease states-especially in IBD. [24][25][26][27][28][29][30] The aim of this review is to summarize recent findings on the role of desmosomes in intestinal epithelial barrier regulation, inflammation and IBD pathogenesis. In the first part, we briefly describe the most important players contributing to intestinal barrier integrity.…”

Section: Introductionmentioning

confidence: 99%

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Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

2020

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Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and Ulcerative colitis (UC) have a complex and multifactorial pathogenesis which is incompletely understood. A typical feature closely associated with clinical symptoms is impaired intestinal epithelial barrier function. Mounting evidence suggests that desmosomes, which together with tight junctions (TJ) and adherens junctions (AJ) form the intestinal epithelial barrier, play a distinct role in IBD pathogenesis. This is based on the finding that desmoglein (Dsg) 2, a cadherin‐type adhesion molecule of desmosomes, is required for maintenance of intestinal barrier properties both in vitro and in vivo, presumably via Dsg2‐mediated regulation of TJ. Mice deficient for intestinal Dsg2 show increased basal permeability and are highly susceptible to experimental colitis. In several cohorts of IBD patients, intestinal protein levels of Dsg2 are reduced and desmosome ultrastructure is altered suggesting that Dsg2 is involved in IBD pathogenesis. In addition to its adhesive function, Dsg2 contributes to enterocyte cohesion and intestinal barrier function. Dsg2 is also involved in enterocyte proliferation, barrier differentiation and induction of apoptosis, in part by regulation of p38MAPK and EGFR signalling. In IBD, the function of Dsg2 appears to be compromised via p38MAPK activation, which is a critical pathway for regulation of desmosomes and is associated with keratin phosphorylation in IBD patients. In this review, the current findings on the role of Dsg2 as a novel promising target to prevent loss of intestinal barrier function in IBD patients are discussed.

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Section: Cellular Component Of the Intestinal Barriermentioning

confidence: 99%

Section: Levels and Desmosome Ultrastructure In Ibdmentioning

confidence: 99%

Section: Role Of Dsg2 In Experimental Colitis and As A Therapeuticmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

2020

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“…All images of sections were obtained using an inverted microscope (Olympus, Tokyo, Japan) with 10× and 20× objective lenses. Two investigators were used to quantify, blindly, the severity of epithelial damage and tissue inflammation in H&E‐stained sections of the colon using epithelial damage score and inflammation score (Erben et al, 2014; Meir et al, 2019). The criteria and scores for severity of epithelial damage were as follows: no epithelial damage = 1, focal lesions = 2, multiple lesions = 3, and extended ulcerations = 4.…”

Section: Methodsmentioning

confidence: 99%

Nutrient‐induced hyperosmosis evokes vasorelaxation via TRPV1 channel‐mediated, endothelium‐dependent, hyperpolarisation in healthy and colitis mice

Guo

Cheng

Zhang

et al. 2020

British J Pharmacology

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Background and Purpose: In humans, blood flow in the mesenteric circulation is greatly increased after meals, but the mechanisms underlying postprandial mesenteric vasorelaxation induced by nutrients and whether this process is involved in the pathogenesis of colitis, are not well understood. Here we have studied the direct actions of nutrients on mesenteric arterial tone and the underlying molecular mechanisms in healthy and colitis mice.Experimental Approach: Colitis in C57BL/6 mice was induced with dextran sodium sulphate. Nutrient-induced vasorelaxation of mesenteric arterioles from humans and mice was studied with wire myograph assays. Ca 2+ and Na + imaging were performed in human vascular endothelial cells and vascular smooth muscle cells, using selective pharmacological agents and shRNA knockdown of TRPV1 channels. Key Results: Glucose, sodium and mannitol concentration-dependently induced endothelium-dependent relaxation of human and mouse mesenteric arterioles via hyperosmotic action,. Hyperosmosis-induced vasorelaxation was almost abolished by selective blockers for TRPV1, IK Ca and SK Ca channels. Glucose markedly stimulated Ca 2+ influx through endothelial TRPV1 channels, an effect attenuated by selective blockers and shRNA knockdown of TRPV1 channels. Capsaicin synergised the glucose-induced vasorelaxation. Nutrient-induced hyperosmosis also activated Na + / K + -ATPase and the Na/Ca exchanger (NCX) to decrease [Ca 2+ ] i in VSMCs. Glucoseinduced vasorelaxation was impaired in mouse colitis. Conclusion and Implications:Nutrient-induced hyperosmosis evoked endotheliumdependent mesenteric vasorelaxation via the TRPV1/Ca 2+ / endothelium-dependent hyperpolarisation pathway to increase normal mucosal perfusion, which is impaired in our model of colitis. The TRPV1/Ca 2+ / endothelium-dependent hyperpolarisation pathway could provide novel drug targets for gastrointestinal diseases with hypoperfusion, such as chronic colitis and mesenteric ischaemia. Abbreviations: 4-AP, 4-aminopyridine; BK Ca , large-conductance Ca 2+ -activated K + ; CDCC, concentration-dependent vasoconstrictive curve; CDRC, concentration-dependent vasorelaxation curve; C max , percentage of the maximum contraction; DSS, dextran sodium sulphate; ECL, enhanced chemiluminescence; EDCFs, endothelium-derived contracting factors; EDH, endotheliumdependent hyperpolarisation; EDRFs, endothelium-derived relaxing factors; H&E, haematoxylin and eosin; HASMCs, human aortic smooth muscle cells; HUVEC, human umbilical vein endothelial cells; IbTX, iberiotoxin; IKCa, intermediate-conductance Ca 2+ -activated K + channels; INDO, indomethacin; L-NNA, N ω -nitro-L-arginine; MOI, multiplicity of infection; NCX, Na + /Ca 2+ exchanger; PSS, physiological salt solution; R max , percentage of the maximum relaxation; SK Ca , small-conductance Ca 2+ -activated K + channels; SmGM, smooth muscle growth medium; TBST, Tris-buffered saline with 0.05% Tween 20; TEA, tetraethylammonium; VGCCs, voltage-gated calcium channels; VSMCs, vascular smooth muscle cells. Yanj...

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In vitro evaluation of periapical lesion‐derived stem cells for dental pulp tissue engineering

Mao

et al. 2021

FEBS Open Bio

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Dental pulp tissue engineering is a promising alternative treatment for pulpitis and periapical periodontitis, and dental pulp stem cells (DPSCs) are considered to be the gold standard for dental seed cell research. Periapical lesions harbor mesenchymal stem cells with the capacity for self‐renewal and multilineage differentiation. However, it remains unknown whether these periapical lesion‐derived stem cells (PLDSCs) are suitable for dental pulp tissue engineering. To investigate this possibility, PLDSCs and DPSCs were isolated using the tissue outgrowth method and cultured under identical conditions. We then performed in vitro experiments to investigate their biological characteristics. Our results indicate that PLDSCs proliferate actively in vitro and exhibit similar morphology, immunophenotype and multilineage differentiation ability as DPSCs. Simultaneously, PLDSCs exhibit stronger migrative ability and express more vascular endothelial growth factor and glial cell line‐derived neurotrophic factor than DPSCs, and PLDSC‐derived conditioned medium was more effective in tube formation assay. The mRNA expression levels of immunomodulatory genes HLA‐G , IDO and ICAM‐1 were also higher in PLDSCs. However, regarding osteo/odontogenic differentiation, PLDSCs showed weaker alkaline phosphatase staining and lower calcified nodule formation compared to DPSCs, as well as lower expression of ALP , RUNX2 and DSPP , as confirmed by a quantitative RT‐PCR. The osteo/odontogenic protein expression levels of DSPP, RUNX2, DMP1 and SP7 were also higher in DPSCs. The present study demonstrates that PLDSCs demonstrate potential use as seed cells for dental pulp regeneration, especially for achieving enhanced neurovascularization.

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Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease

Cited by 68 publications

References 55 publications

Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

Nutrient‐induced hyperosmosis evokes vasorelaxation via TRPV1 channel‐mediated, endothelium‐dependent, hyperpolarisation in healthy and colitis mice

In vitro evaluation of periapical lesion‐derived stem cells for dental pulp tissue engineering

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