Systematic understanding of circadian gene regulation in stem cells

Stem cell-based regenerative medicine represents a transformative therapeutic strategy for refractory diseases. However, clinical implementation is often hindered by poor engraftment, functional immaturity, and heterogeneous outcomes. While physiological homeostasis is regulated by circadian rhythms, a systematic understanding of how donor pathology and culture environments alter the intrinsic clock machinery of stem cells (SCs) remains limited. This review elucidates the molecular mechanisms of clock gene regulation in SCs and the pathways through which disease and aging disrupt these functions. SCs utilize distinct circadian strategies depending on their developmental stage. Pluripotent stem cells (PSCs) actively maintain a “timeless state” to prioritize rapid cell division and ultradian oscillations (e.g. hairy and enhancer of split 7 [HES7] ). This suppression is mediated by multilayered processes: microRNA (miRNA)-mediated post-transcriptional repression of CLOCK, cytoplasmic sequestration of PERIOD (PER) proteins via karyopherin alpha 2 (KPNA2), and epigenetic silencing of brain and muscle ARNT-like 1 (BMAL1) by the polycomb repressive complex 2 (PRC2). In contrast, adult stem cells (ASCs), such as mesenchymal stem cells (MSCs), possess functional molecular clocks. These clocks act as “temporal gatekeepers” that coordinate the cell cycle, genomic stability, and lineage specification. Furthermore, the stem cell niche integrates systemic signals from the suprachiasmatic nucleus (SCN) to provide localized regulatory cues. Clinically, a significant “functional uncoupling” is observed in pathological states. In SCs derived from patients with type 2 diabetes (T2DM), core clock oscillations persist, yet they fail to drive downstream effectors such as mitochondrial metabolism. Aging further triggers circadian reprogramming and impairs the non-standard “moonlighting” role of BMAL1 in maintaining genome integrity by suppressing long interspersed nuclear element-1 (LINE1) retrotransposons, thereby preventing GMP-AMP synthase (cGAS-STING)-mediated inflammaging. These insights suggest that conventional quality assessments based solely on surface markers are insufficient. Evaluating the coupling between circadian machinery and functional outputs should become a critical metric for stem cell therapies. By reframing clock mechanisms as “controllable variables”—through chronotherapy or pre-transplant synchronization—this review provides a framework for next-generation regenerative medicine.