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Mol Cell. 2016 Dec 1;64(5):900-912. doi: 10.1016/j.molcel.2016.10.015. Epub 2016 Nov 17.

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

Author information

1
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA.
2
Department of Mathematical Sciences, University of Cincinnati, Cincinnati, OH 45221-0025, USA.
3
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA.
4
Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
5
Program in Neuroscience, Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL 32306, USA.
6
Department of Neuroscience, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
7
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA. Electronic address: sean.moore@virginia.edu.
8
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267-0576, USA; Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, USA. Electronic address: christian.hong@uc.edu.

Abstract

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.

KEYWORDS:

Paneth cell; WNT signaling; cell cycle; circadian rhythm; coupled oscillators; intercellular coupling; intestinal crypt; intestinal stem cell; progenitor cell

PMID:
27867006
PMCID:
PMC5423461
DOI:
10.1016/j.molcel.2016.10.015
[Indexed for MEDLINE]
Free PMC Article

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