A review of the circadian regulation of stem cells: harnessing the internal body clock for enhanced regenerative therapies.

<h4>Background</h4>Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations that influence their self-renewal, proliferation, and differentiation. Key developmental pathways (Wnt/β-catenin, Notch, and Hedgehog) are increasingly recognized as both regulators and targets of circadian machinery.<h4>Objectives</h4>This review synthesizes current knowledge on the bidirectional crosstalk between circadian clock components and major stem-cell regulatory pathways, and evaluates how this interplay shapes tissue homeostasis, regenerative capacity, and therapeutic potential.<h4>Methods</h4>Literature examining molecular interfaces between circadian clock genes and Wnt, Notch, and Hedgehog signaling was surveyed, with emphasis on transcriptional regulation, chromatin dynamics, post-translational control, and functional outcomes for stem-cell behavior and regeneration.<h4>Results</h4>Evidence indicates that core clock components modulate stem-cell pathways through direct transcriptional control, shared enhancer architecture, altered chromatin accessibility, and rhythmic protein modification. In turn, Wnt, Notch, and Hedgehog signals feed back onto clock genes, influencing circadian amplitude and phase within stem-cell niches. Perturbation of this reciprocal regulation disrupts tissue maintenance, diminishes regenerative responses, alters metabolic equilibrium, and may promote tumorigenesis.<h4>Conclusions</h4>Circadian oscillators act as temporal gatekeepers of stem-cell function. Mapping the molecular interfaces between clock genes and developmental signaling pathways reveals new opportunities to refine regenerative therapies. Chronotherapeutic strategies, i.e. timing interventions to intrinsic circadian phases may enhance the efficacy, precision, and safety of stem-cell-based treatments.