한빛사 논문
Andrew E Rosselot1,†, Miri Park1,†, Mari Kim1,†, Toru Matsu-Ura1, Gang Wu2, Danilo E Flores2, Krithika R Subramanian1, Suengwon Lee1, Nambirajan Sundaram3, Taylor R Broda4, Heather A McCauley4, Jennifer A Hawkins3, Kashish Chetal5, Nathan Salomonis5, Noah F Shroyer6, Michael A Helmrath3,4, James M Wells4,7, John B Hogenesch2,8, Sean R Moore9,* & Christian I Hong1,4,8,10,**
1Department of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
2Division of Human Genetics and Immunobiology, Center for Chronobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
3Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
4Center for Stem Cell and Organoid Medicine, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
6Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
7Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
8Center for Chronobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
9Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA
10Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
*Corresponding author.
**Corresponding author.
†These authors contributed equally to this work.
Abstract
Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed mechanisms regulating circadian physiology of the intestine remain largely unknown. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids possess circadian rhythms and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses to TcdB. RNA-Seq analysis shows that ~3–10% of the detectable transcripts are rhythmically expressed in mouse and human enteroids. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids, and disruption of Rac1 abolishes clock-dependent necrotic cell death responses. Our findings uncover robust functions of circadian rhythms regulating clock-controlled genes in both mouse and human enteroids governing organism-specific, circadian phase-dependent necrotic cell death responses, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications.
Keywords: circadian rhythms; Clostridium difficiletoxin B; human enteroids; intestinal organoids; Rac1
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