Intercellular Coupling of the Cell Cycle and Circadian Clock in Adult Stem Cell Culture

• Published in: Molecular cell Vol. 64; no. 5; pp. 900 - 912
• Main Authors: Matsu-ura, Toru, Dovzhenok, Andrey, Aihara, Eitaro, Rood, Jill, Le, Hung, Ren, Yan, Rosselot, Andrew E., Zhang, Tongli, Lee, Choogon, Obrietan, Karl, Montrose, Marshall H., Lim, Sookkyung, Moore, Sean R., Hong, Christian I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: Adult Stem Cells - physiology; Animals; cell cycle; Cell Cycle - physiology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Circadian Clocks - physiology; Circadian Rhythm; coupled oscillators; intercellular coupling; intestinal crypt; Intestinal Mucosa - physiology; intestinal stem cell; Jejunum - metabolism; Mice; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Organoids; Paneth cell; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; progenitor cell; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Tissue Culture Techniques; WNT signaling; Wnt Signaling Pathway - physiology; Paneth cell; intestinal stem cell; cell cycle; circadian rhythm; coupled oscillators; intercellular coupling; intestinal crypt; progenitor cell; WNT signaling
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.10.015

Circadian clock-gated cell division cycles are observed from cyanobacteria to mammals via intracellular molecular connections between these two oscillators. Here we demonstrate WNT-mediated intercellular coupling between the cell cycle and circadian clock in 3D murine intestinal organoids (enteroids). The circadian clock gates a population of cells with heterogeneous cell-cycle times that emerge as 12-hr synchronized cell division cycles. Remarkably, we observe reduced-amplitude oscillations of circadian rhythms in intestinal stem cells and progenitor cells, indicating an intercellular signal arising from differentiated cells governing circadian clock-dependent synchronized cell division cycles. Stochastic simulations and experimental validations reveal Paneth cell-secreted WNT as the key intercellular coupling component linking the circadian clock and cell cycle in enteroids. [Display omitted] •The circadian clock gates cell-cycle progression in the intestinal epithelium•The circadian clock is less robust in intestinal stem and progenitor cells•WNT secreted from Paneth cells couples the circadian clock and cell cycle Paneth cell-dependent circadian secretion of WNT is a key mechanism linking circadian rhythms and cell-cycle progression in murine enteroids. This finding implicates Paneth cells as local pacemakers that regulate the timing of cell divisions in intestinal stem cells and progenitor cells in the context of circadian rhythmicity.