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

Abstract

Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

1. Introduction

Circadian rhythms are intrinsic 24-h cycles that coordinate physiology with the external environment and arise from the molecular clockwork built on transcription-translation feedback loops [1]. In the core loop, the Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle ARNT-Like 1 (BMAL1) complex activates Period and Cryptochrome genes (PER and CRY). These proteins later form inhibitory complexes that shut down CLOCK & BMAL1 activity and maintain near 24-h periodicity [2]. Secondary loops involving nuclear proteins REV-ERB and Retinoic acid receptor-related Orphan Receptor (ROR) receptors, stabilize this system by regulating Bmal1 transcription [3]. Post-transcriptional regulators, ion fluxes, electrical activity, and metabolic cues add further layers of control. Together, these loops create a robust timing system that aligns cellular and organismal functions with day-night cycles and are central to physiological homeostasis. To illustrate these hierarchical interactions, Fig. 1 summarizes the temporal profiles of cortisol and melatonin, the light-entrained SCN pathway, and the core molecular feedback loops that generate circadian rhythmicity.

Up to fifteen percent of mRNAs in all tissues follow circadian oscillations [4]. These rhythms shape sleep–wake cycles, metabolism, hormone secretion, temperature regulation, and immune activity. They also orchestrate tissue-specific processes, including lipid synthesis in adipose tissue, insulin release in the pancreas, and inflammatory responses in the lung. The SCN, a neuronal cluster in the hypothalamus, serves as the body’s master clock and synchronizes these rhythms across organ systems to maintain coordinated cellular repair, metabolic balance, and energy use [5]. Through signals such as glucocorticoids, it entrains peripheral clocks in stem cells, imposing temporal structure that supports quiescence, proliferation, and tissue regeneration. Peripheral clocks interpret these cues through cell-autonomous transcription-translation feedback loops but lose stability without SCN coordination (Table 1). When this hierarchy is disrupted, risks of metabolic syndrome, cardiovascular disease, diabetes, obesity and immune dysfunction increase. In mouse models, SCN-peripheral misalignment (e.g., chronic jet-lag or shift work) accelerates sarcopenia and muscle functional decline via dysregulated satellite cell responses, uncoupled lipid metabolism, and elevated reactive oxygen species (ROS) [6, 7]. These effects occur despite compensatory regenerative efforts, in which peripheral clocks continue to dominate lineage commitment decisions, including the temporal phasing of Runt-related transcription factor 2 (RUNX2) expression [8].