Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior

An article by Anne-Sophie Delbès, Mar Quiñones, CédricGobet, JulienCastel, Raphaël G. P. Denis, JérémyBerthelet, Benjamin D. Weger, Etienne Challet, Aline Charpagne, Sylviane Metairon, Julie Piccand, Marine Kraus, Bettina H. Rohde, John Bial Elizabeth M. Wilson, Lise-Lotte Vedin, Mirko E. Minniti, Matteo Pedrelli, Paolo Parini,Frédéric Gachon, Serge Luquet

Engraftment of human hepatocyte affects liver rhythmic gene expression.

(A) Model for humanized Fah^−/−, Rag2^−/−, Il2rg^−/− (FRG-KO) that can be repopulated with primary human (red) or murine (black) hepatocytes to produce LHM or LMM mice. (B) Experimental design for liver tissue collection before RNA extraction, sequencing, and analysis according to gene expression rhythmic properties. Alteration of rhythmic gene expression of murine transcript in the liver of LMM and both murine (black, Mu-RNA) and human transcript (red, Hu-RNA) in the liver of LHM mice is assessed by model selection (models 1 to 15): black line, stable transcription; black wave, rhythmic transcription; red or green waves, rhythmic profiles with different rhythmic parameters (i.e., phase and/or amplitude). (C) Heatmaps of normalized rhythmic mRNA levels (BICW > 0.3, log₂ amplitude > 0.5) in the liver of LMM (black) and LHM (black) murine and human transcript (red) in the liver of LMM and LHM. RNA presented here belonged to model 4 where genes were rhythmic only in LMM. (D) Radial plot of the distribution peak phase of expression for genes rhythmic only in the liver of LMM

Abstract

The synchronization of circadian clock depends on a central pacemaker located in the suprachiasmatic nuclei. However, the potential feedback of peripheral signals on the central clock remains poorly characterized. To explore whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. Liver humanization led to reprogrammed diurnal gene expression and advanced the phase of the liver circadian clock that extended to muscle and the entire rhythmic physiology. Similar to clock-deficient mice, liver-humanized mice shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that hepatocyte clocks can affect the central pacemaker and offer potential perspectives to apprehend pathologies associated with altered circadian physiology.

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A new article from Cécile Haumaitre and collaborators discusses the origin of pancreatic lesions associated with pancreatic cancer

Diabetes Institute, From inflammation to cancer in digestive diseases, Publications

Pancreatic ductal adenocarcinoma is currently the fourth leading cause of cancer death worldwide. It is projected to become the second leading cause of cancer death by 2030. Unfortunately, PDAC is often diagnosed at an advanced stage, resulting in a 5-year survival rate of less than 10%. Since the most common precancerous lesions of PDAC are currently not clinically detectable, understanding the mechanisms that lead to their formation and progression is crucial to enabling early diagnosis and more effective therapeutic intervention.