scholarly journals NOD2 Supports Crypt Survival and Epithelial Regeneration after Radiation-Induced Injury

2019 ◽  
Vol 20 (17) ◽  
pp. 4297 ◽  
Author(s):  
Chansu Lee ◽  
Changhoon Choi ◽  
Ho Suk Kang ◽  
Sung-Won Shin ◽  
Shin-Yeong Kim ◽  
...  
Keyword(s):  
Survival Rate ◽  
3D Culture ◽  
Irradiation Damage ◽  
Intestinal Epithelial ◽  
Cell Protection ◽  
Epithelial Regeneration ◽  
Radiation Induced ◽  
Regeneration Capability ◽  
Lethal Irradiation ◽  
Oligomerization Domain

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) affords stem cell protection and links microbes to intestinal epithelial regeneration. We investigated whether NOD2 status is associated with crypt survival and intestinal epithelial regeneration independent of microbiota-derived molecules. To assess crypt survival, a clonogenic microcolony assay was performed with 15 Gy of X-ray irradiation. The fractional crypt survival rate (46.0 ± 15.5% vs. 24.7 ± 9.2%, p < 0.01) and fractional EdU-positive crypt survival rate (29.8 ± 14.5% vs. 9.79 ± 4.37%, p = 0.015) were significantly decreased in the NOD2−/− mice compared with the wild-type (WT) mice at 3.5 days after irradiation. To evaluate intestinal epithelial regeneration capability, organoid reconstitution assays were performed. Small bowel crypts of the WT and NOD2−/− mice were isolated and seeded into Matrigel for 3D culture. In the organoid reconstitution assays, the number of organoids formed did not differ between the NOD2−/− and WT mice. Organoid formation ability was also assessed after exposure to 5 Gy irradiation. Organoid formation ability was significantly decreased in the NOD2−/− mice compared with the WT ones after exposure to 5 Gy irradiation (33.2 ± 5.9 vs. 19.7 ± 8.8/well, p < 0.01). NOD2 supports crypt survival after potentially lethal irradiation damage and is associated with intestinal epithelial regeneration.

scholarly journals IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

2017 ◽  
Vol 214 (2) ◽  
pp. 423-437 ◽  
Author(s):  
Michaela A. Diamanti ◽  
Jalaj Gupta ◽  
Moritz Bennecke ◽  
Tiago De Oliveira ◽  
Mallika Ramakrishnan ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
Epithelial Regeneration ◽  
Iκb Kinase ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Protein Response ◽  
Oligomerization Domain

Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.

The growth promoting effect of mammalian thioredoxin and the redox regulation of intestinal epithelial regeneration

2000 ◽  
Vol 118 (4) ◽  
pp. A602
Author(s):  
Shigeo Takaishi ◽  
Mitsutaka Sawada ◽  
Yukari Morita ◽  
Hiroaki Fukuzawa ◽  
Hiroshi Seno ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Intestinal Epithelial ◽  
Promoting Effect ◽  
Epithelial Regeneration ◽  
Growth Promoting

Sa1436 RNA-Binding Protein HuR Regulates Intestinal Epithelial Regeneration by Altering Subcellular Distribution of Rac1

2016 ◽  
Vol 150 (4) ◽  
pp. S314-S315
Author(s):  
Lan Liu ◽  
Rao N. Jaladanki ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
Jing Wu ◽  
...  
Keyword(s):  
Subcellular Distribution ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Intestinal Epithelial ◽  
Epithelial Regeneration

scholarly journals Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation

2012 ◽  
Vol 302 (10) ◽  
pp. G1111-G1132 ◽  
Author(s):  
Laurianne Van Landeghem ◽  
M. Agostina Santoro ◽  
Adrienne E. Krebs ◽  
Amanda T. Mah ◽  
Jeffrey J. Dehmer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Populations ◽  
Intestinal Epithelial ◽  
P53 Signaling ◽  
Reporter Mice ◽  
Radiation Induced ◽  
Molecular Phenotypes ◽  
Stem Cell Populations ◽  
Induced Changes

Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.

fMLP induces Hsp27 expression, attenuates NF-κB activation, and confers intestinal epithelial cell protection

2007 ◽  
Vol 292 (4) ◽  
pp. G1070-G1078 ◽  
Author(s):  
Ryan M. Carlson ◽  
Stephan R. Vavricka ◽  
Jyrki J. Eloranta ◽  
Mark W. Musch ◽  
Donna L. Arvans ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Target Genes ◽  
Bacterial Flora ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Cell Protection ◽  
Hsp27 Expression ◽  
Tnf Α

Sustained expression of cytoprotective intestinal epithelial heat shock proteins (Hsps), particularly Hsp27, depends on stimuli derived from bacterial flora. In this study, we examined the role of the bacterial chemotactic peptide fMLP in stimulating colonic epithelial Hsp expression at concentrations encountered in a physiological milieu. Treatment of the polarized human intestinal epithelial cell line Caco2bbe with physiological concentrations of fMLP (10–100 nM) induced expression of Hsp27, but not Hsp72, in a time- and concentration-dependent manner. Induction of Hsp27 by fMLP was specific since the fMLP analogs MRP and MLP were not effective. Hsp27 induction by fMLP was blocked by the fMLP-receptor antagonist BOC-FLFLF and was blocked when the dipeptide transporter PepT1, an entry pathway for fMLP, was silenced. fMLP activated both the p38 and ERK1/2 MAP kinase pathways in Caco2bbe cells, but not the SAPK/JNK pathway. The p38 inhibitor SB203580, but not the MEK-1 inhibitor PD98059, blocked Hsp27 induction by fMLP. fMLP treatment inhibited actin depolymerization and decreased transepithelial resistance caused by the oxidant monochloramine, and this inhibition was reversed by silencing Hsp27 expression. fMLP pretreatment also inhibited activation of proinflammatory transcription factor NF-κB by TNF-α in Caco2bbe cells, reducing induction of NF-κB target genes by TNF-α both in human intestinal biopsies and Caco2bbe cells. In conclusion, fMLP may contribute to the maintenance of intestinal homeostasis by mediating physiological expression of Hsp27, enhancing cellular protection, and negatively regulating the inflammatory response.

scholarly journals Inflammation- and Gut-Homing Macrophages, Engineered to De Novo Overexpress Active Vitamin D, Promoted the Regenerative Function of Intestinal Stem Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9516
Author(s):  
Yi Xu ◽  
David J. Baylink ◽  
Huynh Cao ◽  
Jeffrey Xiao ◽  
Maisa I. Abdalla ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vitamin D ◽  
De Novo ◽  
Chronic Inflammatory Disease ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Active Vitamin ◽  
Gut Inflammation ◽  
Epithelial Regeneration ◽  
Active Vitamin D

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.

Weissella paramesenteroides WpK4 ameliorate the experimental amoebic colitis by increasing the expression of MUC‐2 and the intestinal epithelial regeneration

2020 ◽  
Vol 129 (6) ◽  
pp. 1706-1719 ◽  
Author(s):  
G.K.S. Prado ◽  
K.C. Torrinha ◽  
R.E. Cruz ◽  
A.B.B. Gonçalves ◽  
C.A.V. Silva ◽  
...  
Keyword(s):  
Intestinal Epithelial ◽  
Epithelial Regeneration ◽  
Amoebic Colitis
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