Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration

Abstract

The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5+ stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2-deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration.

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…Several lines of evidence indicate that Notch signaling is active in multipotent ISCs [25–27]. Recent analysis of intestine-specific deletion of Notch receptors shows Notch1 is the primary receptor regulating ISC function, but Notch1 and Notch2 regulate cell proliferation, cell fate specification, and post-injury regeneration [28, 29]. Additional Notch inhibitor studies have demonstrated Notch directly targets Lgr5+ CBCs and is required for stem cell proliferation and survival, in an Atoh1-independent manner [28, 30, 31].…”

“…Recent analysis of intestine-specific deletion of Notch receptors shows Notch1 is the primary receptor regulating ISC function, but Notch1 and Notch2 regulate cell proliferation, cell fate specification, and post-injury regeneration [28, 29]. Additional Notch inhibitor studies have demonstrated Notch directly targets Lgr5+ CBCs and is required for stem cell proliferation and survival, in an Atoh1-independent manner [28, 30, 31]. Moreover, Paneth cells and numerous cell types located in the lamina propria such as pericryptal myofibroblasts and immune cells are thought to contribute essential signals to maintain the stem cell niche (Figure 2).…”

Kolostruma Cevap Veren Rat Yavrularında İntrauterin Büyüme Geriliği İntestinal Otofaji ve Proliferayonu Artırır

“…It has been documented that autophagy regulates differentiation via notch signaling pathway [45] . Therefore, enhanced intestinal autophagy under low-stress conditions after feeding with sufficient colostrum may enhance the proliferation of intestinal crypt base columnar stem cells and improve the crypt regeneration [46,47] . In consistence with these results, the ki67 mRNA expression tended to increase in the jejunum of IUGR pups fed with colostrum in present study.…”

Epigenetic regulation of the intestinal epithelium

“…Notch signaling opposes Atoh1 activation to direct cell fate into the enterocyte lineage. Loss of Notch signaling causes increased secretory cell differentiation along the crypt-villus axis, either through use of γ-secretase inhibitors (123, 124), or by ablation of Notch receptors (125, 126), Dll ligands (127), or CSL/RBP-κ (123). Combined loss of Notch signaling and Atoh1 expression blocks secretory cell fate conversion (124, 128–130) and induces global enterocyte differentiation (130), establishing that Notch acts specifically through that Atoh1 to regulate secretory cell fate, and that active Notch is not required for enterocyte differentiation.…”

“…Notch pathway inhibition decreases expression of CBC stem cell marker genes, including Olfm4 and Lgr5 (124, 126, 127). VanDussen and colleagues found that the NICD directly activates expression of Olfm4, demonstrating the crucial function of Notch signaling in maintaining the CBC stem cell population (124).…”