Organoids as Model Systems to Investigate Circadian Clock-Related Diseases and Treatments

Circadian rhythms exist in most cell types in mammals regulating temporal organization of numerous cellular and physiological processes ranging from cell cycle to metabolism. The master clock, suprachiasmatic nucleus (SCN) in the hypothalamus, processes light input and coordinates peripheral clocks optimizing organisms' survival and functions aligning with external conditions. Intriguingly, it was demonstrated that circadian rhythms in the mouse liver can be decoupled from the master clock under time-restricted feeding regimen when food was provided during their inactive phase. Furthermore, mouse liver showed clock-controlled gene expression even in the absence of the master clock demonstrating independent functions of peripheral clocks apart from the SCN. These findings suggest a dynamic relationship between the master and peripheral clocks and highlight potential functions of peripheral clocks independent of the master clock. Importantly, disruption of circadian rhythms correlates with numerous human ailments including cancer and metabolic diseases, suggesting that diseases may be exacerbated by disruption of circadian rhythms in the SCN and/or peripheral clocks. However, molecular mechanisms providing causative links between circadian rhythms and human diseases remain largely unknown. Recent technical advances highlighted PCS- and tissue-derived 3-dimensional organoids as in vitro organs that possess numerous applications ranging from disease modeling to drug screening. In this mini-review, we highlight recent findings on the importance and contributions of peripheral clocks and potential uses of 3D organoids investigating complex circadian clock-related diseases.