Crosstalk between the circadian clock, intestinal stem cell niche, and epithelial cell fate decision

Abstract

The circadian rhythm, a 24-h cycle, plays a crucial role in regulating gut physiological processes, particularly the proliferation and differentiation of intestinal epithelial cells, which are essential for gut homeostasis and repair. This review discusses the complex interactions between circadian rhythms, cell cycle regulation, and key signaling pathways (Wnt, Notch, and Hippo) in the context of the intestinal stem cell niche and epithelial cell fate decisions. Key molecules such as brain and muscle ARNT-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), hairy and enhancer of split 1 (Hes1), and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) coordinate stem cell functions with circadian rhythms. We discuss how Notch signaling regulates the cell cycle and interacts with circadian rhythms. Additionally, we explore the role of Hippo-Wnt signaling in balancing cell proliferation and differentiation. Furthermore, we highlight the intricate relationships between circadian clock components and signaling pathways, emphasizing the importance of temporal coordination in determining epithelial cell fate. We also discuss shared enzymes, including casein kinase 1 delta (CK1δ), glycogen synthase kinase 3 (GSK3), and AMP-activated protein kinase (AMPK), which play a role in regulating the cell cycle, circadian rhythm, and signaling pathways. In summary, this review offers valuable insights into the regulatory mechanisms that control stem cell behavior and epithelial cell differentiation, suggesting promising directions for future research in intestinal biology and tissue homeostasis.

Keywords: Cell cycle regulation; Circadian clock; Epithelial differentiation; Intestinal stem cell; Signaling pathways.

Figure 1

The signaling pathways involved in the intestinal stem cell niche and cell fate determination. Wnt, Notch, and BMP signals show spatial gradients along the crypt–villus axis. Lgr5⁺ crypt base columnar (CBC) cell and +4 stem cell pools located at the crypt base are surrounded by mesenchymal cells that produce and release niche-associated factors.

Figure 2

Types of intestinal epithelial cells with their specific expression (indicated by dashed boxes), along with the factors that initiate differentiation. The crypt–villus axis includes the stem cell compartment, transit-amplifying (TA) cell compartment, and differentiation compartment. Differentiated cell types comprise M cells, absorptive cells (enterocytes), and secretory cells (tuft cells, Paneth cells, goblet cells, and enteroendocrine cells). The “∗” symbol denotes specific expression to the human intestine.

Figure 3

A schematic representation of the bidirectional relationship between the cell cycle and the circadian clock. Genes such as Wee1, Gadd45, c-Myc, Cyclind1, Cyclinb, P21, and P16 are directly or indirectly related to the circadian clock and significantly impact the cell cycle. Wee1 and GADD45 inhibit cyclin B-CDK1, whereas c-Myc inhibits p15/p21/p27. P16 inhibits cyclin D–CDK4/6, and p21 inhibits cyclin B–CDK1, cyclin D–CDK4/6, and cyclin E–CDK2. Cyclin D1 and cyclin B are active during the G1/S and G2/M phases, respectively. BMAL1/CLOCK target gene c-Myc regulates key clock proteins, including PER1, BMAL1, and REV-ERB. The link between the circadian clock and the cell cycle involves p53, which activates GADD45A and itself. Activation, inhibition, and potential regulation are denoted by arrows, blunt ends, and dashed lines, respectively.

Figure 4

A schematic illustration of interactions among the Wnt signaling pathway, circadian clock, and cell cycle. Wnt target genes such as c-Myc and CyclinD1 play essential roles in both the circadian clock and cell cycle. Key Wnt signaling components, including GSK3 and β-catenin, regulate clock proteins and cyclins. The circadian clock can influence Wnt signaling through CSNK1D, BMAL1, and CRY. Cyclin Y phosphorylates LRP6, linking cell cycle activation with Wnt signaling. Activation, inhibition, and potential regulatory relationships are represented by arrows, blunt ends, and dashed lines, respectively.

Figure 5

The interaction map of the Hippo, Wnt, and Notch signaling pathways and their crosstalk with the circadian clock and cell cycle. The schematic highlights how these signaling pathways cooperate or antagonize one other to regulate cell proliferation and differentiation. Activation, inhibition, and potential regulation are illustrated with arrows, blunt ends, and dashed lines, respectively.