RANK drives structured intestinal epithelial expansion during pregnancy.

Autor: Onji M; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria. masahiro.onji@meduniwien.ac.at.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. masahiro.onji@meduniwien.ac.at., Sigl V; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Lendl T; Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria., Novatchkova M; Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria., Ullate-Agote A; Biomedical Engineering Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain., Andersson-Rolf A; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center, Utrecht, The Netherlands., Kozieradzki I; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada., Koglgruber R; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Pai TP; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Lichtscheidl D; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Nayak K; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Zilbauer M; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals (CUH), Addenbrooke's, Cambridge, UK., Carranza García NA; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada., Sievers LK; Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany., Falk-Paulsen M; Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany., Cronin SJF; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Hagelkruys A; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Sawa S; Division of Mucosal Immunology, Research Center for Systems Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan., Osborne LC; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada., Rosenstiel P; Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany., Pasparakis M; Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany., Ruland J; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine and Health, TUM University Hospital, Munich, Germany.; Center for Translational Cancer Research (TranslaTUM), Munich, Germany., Takayanagi H; Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan., Clevers H; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center, Utrecht, The Netherlands.; The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Roche innovation Centre, Basel, Switzerland., Koo BK; Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of Korea., Penninger JM; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria. josef.penninger@helmholtz-hzi.de.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. josef.penninger@helmholtz-hzi.de.; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. josef.penninger@helmholtz-hzi.de.; Helmholtz Centre for Infection Research, Braunschweig, Germany. josef.penninger@helmholtz-hzi.de.
Jazyk: angličtina
Zdroj: Nature [Nature] 2025 Jan; Vol. 637 (8044), pp. 156-166. Date of Electronic Publication: 2024 Dec 04.
DOI: 10.1038/s41586-024-08284-1
Abstrakt: During reproduction, multiple species such as insects and all mammals undergo extensive physiological and morphological adaptions to ensure health and survival of the mother and optimal development of the offspring. Here we report that the intestinal epithelium undergoes expansion during pregnancy and lactation in mammals. This enlargement of the intestinal surface area results in a novel geometry of expanded villi. Receptor activator of nuclear factor-κΒ (RANK, encoded by TNFRSF11A) and its ligand RANKL were identified as a molecular pathway involved in this villous expansion of the small intestine in vivo in mice and in intestinal mouse and human organoids. Mechanistically, RANK-RANKL protects gut epithelial cells from cell death and controls the intestinal stem cell niche through BMP receptor signalling, resulting in the elongation of villi and a prominent increase in the intestinal surface. As a transgenerational consequence, babies born to female mice that lack Rank in the intestinal epithelium show reduced weight and develop glucose intolerance after metabolic stress. Whereas gut epithelial remodelling in pregnancy/lactation is reversible, constitutive expression of an active form of RANK is sufficient to drive intestinal expansion followed by loss of villi and stem cells, and prevents the formation of Apc min -driven small intestinal stem cell tumours. These data identify RANK-RANKL as a pathway that drives intestinal epithelial expansion in pregnancy/lactation, one of the most elusive and fundamental tissue remodelling events in mammalian life history and evolution.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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