A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal

Abstract

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast‐cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent‐based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch‐mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.

Notch signaling activation induces cell death in MAPKi‐resistant melanoma cells

“…In NICD1‐transduced cells, endogenous NOTCH1 expression was also upregulated consistent with the positive feedback regulation of Notch signaling (Chen et al, ) (Supporting information Figure b). Although upregulation of endogenous NOTCH1 protein is comparable in both the MAPKi‐sensitive and MAPKi‐resistant cells, there was no corresponding increase in NICD1 in the MAPKi‐resistant cells (unlike in the MAPKi‐sensitive cells), suggesting that additional mechanism(s) are involved in the regulation of NICD1 levels in MAPKi‐resistant cells (Supporting information Figure b).…”

Lactobacillus acidophilus Alleviated Salmonella‐Induced Goblet Cells Loss and Colitis by Notch Pathway

“…Typically, active Notch signaling results in transcription of a first tier of genes of the Hairy/Enhancer of split class that encode transcriptional repressors. Math1 directly governs goblet cells differentiation, and HES1 suppresses Math1 expression . A previous study demonstrated that mice deficient in Math1 lacked goblet cells, and their epithelial cells continued to maintain their proliferative state .…”

Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging

“…( c ) Schematic (modified from Chen et al . 25 ) of two-photon microscope showing two different laser paths used for both imaging and ablation. ( d ) In vivo two-photon microscopy images of a crypt at different magnifications in Lgr5-GFP mice expressing GFP in stem cells at the crypt base (green).…”

“…The final patterns differed from those prior to ablation, suggesting that the arrangement is defined by interactions between the Paneth and stem cells, rather than dictated by the underlying mesenchymal cells. Signaling, such as Wnt/Notch, involved in maintaining stemness may also play a role in regulating this dynamic positioning 4 , 25 , 32 , 33 . Lgr5-GFP labeling remained consistently bright through two hours (Fig.…”