Science Advances · 21 authors, 14 centres
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In chimeric mice where liver cells were replaced with human hepatocytes, the humanized liver clock advanced the phase and shortened the period of the animals' overall rhythmic physiology and behavior, indicating that peripheral organ clocks can influence the central brain pacemaker.
The study used a chimeric mouse model where mouse hepatocytes were replaced with human hepatocytes (liver-humanized mice, LHM) to test if peripheral clocks feedback on the central pacemaker. The humanization reprogrammed diurnal gene expression in the liver, advancing its circadian phase. This phase advance extended to distant muscle tissue and the entire rhythmic physiology and behavior of the mice. LHM showed a shorter free-running period under constant darkness and shifted their rhythmic physiology more rapidly to the light phase under a day-feeding schedule, similar to clock-deficient mice. The authors conclude that hepatocyte clocks can affect the central pacemaker, challenging the strict hierarchy of the circadian system.
