Liu Ji, Jiang Zhihui, Zha Juanmin, Lin Qiong, He Weiqi
Department of Gastroenterology, Children's Hospital of Soochow University, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genomic Resource Center, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
Genes Dis. 2025 Apr 18;12(6):101650. doi: 10.1016/j.gendis.2025.101650. eCollection 2025 Nov.
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.
昼夜节律，即一个24小时的周期，在调节肠道生理过程中起着关键作用，尤其是对肠道上皮细胞的增殖和分化，而这些过程对于肠道内环境稳定和修复至关重要。本综述讨论了在肠道干细胞生态位和上皮细胞命运决定的背景下，昼夜节律、细胞周期调控以及关键信号通路（Wnt、Notch和Hippo）之间的复杂相互作用。诸如脑和肌肉芳香烃受体核转位蛋白样1（BMAL1）、昼夜运动输出周期蛋白（CLOCK）、毛状分裂增强子1（Hes1）以及Yes相关蛋白/含PDZ结合基序的转录共激活因子（YAP/TAZ）等关键分子，将干细胞功能与昼夜节律协调起来。我们讨论了Notch信号通路如何调节细胞周期并与昼夜节律相互作用。此外，我们探讨了Hippo-Wnt信号通路在平衡细胞增殖和分化中的作用。再者，我们强调了昼夜节律时钟组件与信号通路之间的复杂关系，突出了时间协调在决定上皮细胞命运中的重要性。我们还讨论了包括酪蛋白激酶1δ（CK1δ）、糖原合酶激酶3（GSK3）和AMP激活的蛋白激酶（AMPK）在内的共享酶，它们在调节细胞周期、昼夜节律和信号通路中发挥作用。总之，本综述为控制干细胞行为和上皮细胞分化的调控机制提供了有价值的见解，为肠道生物学和组织内环境稳定的未来研究指明了有前景的方向。
