Decoding the impact of circadian rhythms on intestinal stem cell function

The interplay between the circadian clock, intestinal stem cell niche, and epithelial cell fate is shaping our understanding of how gut homeostasis and cellular regeneration are regulated. Recent insights reveal that the circadian rhythm, a fundamental 24-hour cycle regulating numerous physiological functions, plays a crucial role in maintaining intestinal health by coordinating the proliferation and differentiation of intestinal epithelial cells.

The intestinal epithelium is highly dynamic, undergoing constant renewal to maintain tissue integrity. At the heart of this process are the intestinal stem cells (ISCs), which give rise to various epithelial cell types. The differentiation and fate of these cells are influenced by intricate interactions between the circadian clock, cell cycle, and key signaling pathways such as Wnt, Notch, and Hippo. These pathways regulate the balance between cell proliferation and differentiation, ensuring efficient epithelial renewal and gut homeostasis.

One of the most significant findings is the crosstalk between the circadian clock and cell cycle regulation. Disruptions in the circadian rhythm, caused by factors like jet lag, shift work, or irregular sleep patterns, can impair intestinal stem cell function, leading to reduced regenerative capacity and epithelial instability. In this context, the Wnt signaling pathway emerges as a pivotal link, as it regulates both stem cell proliferation and cell cycle progression. During cell division, circadian proteins like BMAL1 and PER2 modulate Wnt activity, maintaining a rhythmic pattern essential for tissue repair.

Furthermore, the Notch signaling pathway interacts with the circadian clock to control cell fate decisions within the intestinal crypts. By promoting the differentiation of absorptive cells and inhibiting secretory lineages, Notch signaling helps maintain epithelial balance. Circadian regulation of Notch target genes, such as Hes1, ensures that stem cell division and cell differentiation are synchronized with the body's natural rhythms.

The Hippo pathway also plays a critical role, influencing stem cell proliferation by regulating the activity of YAP/TAZ transcription factors. When circadian disruption occurs, altered Hippo signaling can lead to uncontrolled cell growth, increasing the risk of intestinal disorders and even cancer. Maintaining circadian balance is, therefore, crucial for preserving intestinal health and preventing pathological conditions.

By integrating knowledge of circadian biology with the regulation of intestinal stem cells, researchers are paving the way for therapeutic strategies aimed at enhancing gut regeneration and preventing circadian disruption-related diseases. Understanding how the circadian clock influences epithelial cell dynamics could lead to novel interventions targeting intestinal disorders and improving patient outcomes.

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Reference

Ji Liu, Zhihui Jiang, Juanmin Zha, Qiong Lin, Weiqi He, Crosstalk between the circadian clock, intestinal stem cell niche, and epithelial cell fate decision, Genes & Diseases, Volume 12, Issue 6, 2025, 101650, https://doi.org/10.1016/j.gendis.2025.101650

Funding

Natural Science Foundation of Jiangsu Province, China BK20241919

National Natural Science Foundation of China 31971062

Health Promotion Project (China) BJHA-CRP-084

Senior Talent Research Program of "Western Medicine learning Traditional Chinese Medicine" in Jiangsu Province, China

International Joint Research Center for Genomic Resources (China) 2017B01012