The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

Abstract

The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its neighbours in mitotically active states.

Indomethacin and juglone inhibit inflammatory molecules to induce apoptosis in colon cancer cells

“…[38][39][40][41] The results obtained in this study show that indomethacin, juglone, and cotreatment of these two drugs, exhibits their action, presumably, by downregulating the inflammatory mediators, inhibiting the activation of antiapoptotic molecules and increasing the levels of proapoptotic molecules to induce apoptosis in HT29 cells. [45] It has been previously reported that the overexpression of Notch signaling alone does not contribute to cancer initiation; however, cross-talk between the Wnt and Notch pathways is known to increase the risk of cancer initiation [42,46] ; while, their interaction with PPARγ decreases the risk of oncogenic upregulation upon its activation by an external drug as a ligand. [42,43] Activation of the Wnt signaling pathway leads to aberrant translocation of β-catenin and initiating tumor progression through the upregulation of its target genes such as cyclin D1, c-jun, c-Myc, and fra-1.…”

Rotational 3D mechanogenomic Turing patterns of human colon Caco-2 cells during differentiation

“…We observed down-regulation of HES1 by psychological stress level of glucocorticoids, HES1 deficiency resulted increased goblet cell population, altered colon crypts morphology and impaired gut homeostasis which conform to the mathematical model [5, 9, 59]. These features indicate that the HES1 promoter is also a potential crosstalk hub of Notch-GC interactions in colon crypts [5, 60]. The levels of these opposite transcription factors are coupled with tight junction protein levels.…”

“…1,11). Recent mathematical models confirmed that HES1 promoter is the crosstalk hub in Notch-Wnt interactions of the intestinal crypts, our recent study also suggested that physiological glucocorticoid (GC) signal can affect HES1 expression via HES1 promoter negative glucocorticoid response element (GRE) [5, 59, 60]. We observed down-regulation of HES1 by psychological stress level of glucocorticoids, HES1 deficiency resulted increased goblet cell population, altered colon crypts morphology and impaired gut homeostasis which conform to the mathematical model [5, 9, 59].…”

Unraveling the Control of Cell Cycle Periods during Intestinal Stem Cell Differentiation

“…There are, however, many detailed mathematical models of ISCs, some of which have been developed and validated against experimental data (34)(35)(36)(37). Additional models can be found in the reviews by Kershaw Compared with these models, our model is purposely simplified to unravel the complex dynamics that govern cell proliferation during differentiation.…”