Impact of circadian rhythm on differentiation and maturation of insulin-producing cells.

As a promising therapeutic strategy for diabetes, research on differentiating pluripotent stem cell-derived pancreatic beta cells to replace somatic beta cells has been widely pursued. However, despite advances in differentiation protocols, generating fully mature glucose-responsive beta cells remains a significant challenge. Endocrine lineage commitment, particularly towards insulin-secreting beta cells, requires precise temporal and spatial regulation of each signaling pathway that mimic pancreatic development. Although stepwise induction strategies have been developed to recapitulate embryonic stages, differentiated cells often fall short of matching the functionality of native islets. One of the major hurdles lies in achieving proper maturation capable of timely insulin secretion in response to glucose. Recent studies suggested that the intrinsic circadian clock within cells may play a critical role in overcoming this maturation hurdle. Circadian rhythms, generated by auto-feedback loops, are known to coordinate various physiological processes, including metabolism and hormonal secretion. Emerging evidence indicates that the re-organization or synchronizing of circadian oscillations during PSC differentiation could enhance the functionality of beta cells. This review summarized the current understanding of how circadian rhythms intersect with organ development, with a focus on the pancreas. We further discuss the functional implications of circadian gene expression during beta cell differentiation and maturation, highlighting recent advances and remaining challenges in the field.