Abnormal differentiation of intestinal epithelium and intestinal barrier dysfunction in diabetic mice associated with depressed Notch/NICD transduction in Notch/Hes1 signal pathway

Abstract

Proliferative change and intestinal barrier dysfunction in intestinal mucosa of diabetes have been described, but the differentiation characteristics of intestinal epithelial cells (IECs) and the mechanisms in the IECs development remain unclear. To explore the intestinal epithelial constitution patterns and barrier function, the diabetic mouse model was induced by streptozotocin. Tight junctions between IECs were significantly damaged and the serum level of D-lactate was raised in diabetic mice (P < 0.05). The expression of Zo1 and Ocln in the small intestine of diabetic mice were lower, while the markers for absorptive cell (SI) and Paneth cell (Lyz1) were significantly higher than in control mice (P < 0.05). The expression of Msi1, Notch1, and Dll1 in small intestine gradually increased throughout the course of hyperglycemia in diabetic mice (P < 0.05). However, the expression of NICD, RBP-jκ, Math1, and Hes1 had a reverse trend compared with Msi1 and Notch1. Intestinal absorptive cells and Paneth cells had a high proliferation rate in diabetic mice. However, the intestinal barrier dysfunction associated with the decreased expressions of Zo1 and Ocln was detected throughout hyperglycemia. In conclusion, downregulation of Notch/Hes1 signal pathway caused by depressed Notch/NICD transduction is associated with the abnormal differentiation of IECs and intestinal barrier dysfunction in diabetic mice.

Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate

“…There are numerous studies demonstrating that Notch1 regulates the intestinal barrier. (Turgeon et al, 2013, Mathern et al, 2014, Min et al, 2014, Obata et al, 2012, Dahan et al, 2011) siRNA knockdown of Notch1 in vitro (i.e., Caco-2 cells) is associated with impaired intestinal cell monolayer integrity and decreased expression of the tight junction protein occludin. (Dahan et al, 2011) Downregulation of Notch1 in vivo is associated with gut leakiness and alterations in tight junction protein expression and colon inflammation.…”

“…(Dahan et al, 2011) Downregulation of Notch1 in vivo is associated with gut leakiness and alterations in tight junction protein expression and colon inflammation. (Mathern et al, 2014, Dahan et al, 2011, Min et al, 2014) Notch1 cleavage product NICD pairs with the transcription factor Rbpj in mice to activate canonical Notch1 target genes and in vivo knockout of Rbpj in mice causes intestinal hyperpermeability and colitis. (Obata et al, 2012) A recent study in diabetic mice showed that decreased NICD/Hes1 expression resulted in intestinal hyperpermeability.…”

“…(Obata et al, 2012) A recent study in diabetic mice showed that decreased NICD/Hes1 expression resulted in intestinal hyperpermeability. (Min et al, 2014) Significantly, a rectal enema containing siRNA to Notch1 administered to mice reduces colonic stem cell Notch1 expression and results in colonic hyperpermeability. (Mathern et al, 2014) Taken together, these data demonstrate that Notch1 regulates intestinal/colonic barrier integrity and supports alcohol-induced suppression of Notch1 as a potential mechanism contributing to alcohol-induced colonic hyperpermeability.…”

“…Therefore, effects on the stem cells, such as alcohol-induced suppression of Notch1 signaling, could potentially dysregulate epithelial cell differentiation, disrupting the mucosal barrier function as recently shown for decreased intestinal Notch1 signaling in diabetic mice. (Min et al, 2014)…”

Sox9 transcriptionally regulates Wnt signaling in intestinal epithelial stem cells in hypomethylated crypts in the diabetic state

“…IESCs produce progenitors and differentiated cells. The length of the crypt-villus unit is significantly increased in 4- to 10-week-old diabetic mice, with increased proliferation labeling indexes in the small intestine [1]. Furthermore, the proportion of cells positive for leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), which represent bona fide stem cells limited to the IESCs [2], is markedly increased in the crypts of diabetic mice [3].…”