RANK drives structured intestinal epithelial expansion during pregnancy

Masahiro Onji (), Verena Sigl, Thomas Lendl, Maria Novatchkova, Asier Ullate-Agote, Amanda Andersson-Rolf, Ivona Kozieradzki, Rubina Koglgruber, Tsung-Pin Pai, Dominic Lichtscheidl, Komal Nayak, Matthias Zilbauer, Natalia A. Carranza García, Laura Katharina Sievers, Maren Falk-Paulsen, Shane J. F. Cronin, Astrid Hagelkruys, Shinichiro Sawa, Lisa C. Osborne, Philip Rosenstiel, Manolis Pasparakis, Jürgen Ruland, Hiroshi Takayanagi, Hans Clevers, Bon-Kyoung Koo and Josef M. Penninger ()
Additional contact information
Masahiro Onji: Vienna BioCenter (VBC)
Verena Sigl: Vienna BioCenter (VBC)
Thomas Lendl: Vienna BioCenter (VBC)
Maria Novatchkova: Vienna BioCenter (VBC)
Asier Ullate-Agote: Center for Applied Medical Research (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA)
Amanda Andersson-Rolf: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center
Ivona Kozieradzki: University of British Columbia
Rubina Koglgruber: Vienna BioCenter (VBC)
Tsung-Pin Pai: Vienna BioCenter (VBC)
Dominic Lichtscheidl: Vienna BioCenter (VBC)
Komal Nayak: University of Cambridge
Matthias Zilbauer: University of Cambridge
Natalia A. Carranza García: University of British Columbia
Laura Katharina Sievers: Kiel University and University Hospital Schleswig-Holstein
Maren Falk-Paulsen: Kiel University and University Hospital Schleswig-Holstein
Shane J. F. Cronin: Vienna BioCenter (VBC)
Astrid Hagelkruys: Vienna BioCenter (VBC)
Shinichiro Sawa: Kyushu University
Lisa C. Osborne: University of British Columbia
Philip Rosenstiel: Kiel University and University Hospital Schleswig-Holstein
Manolis Pasparakis: University of Cologne
Jürgen Ruland: TUM University Hospital
Hiroshi Takayanagi: University of Tokyo
Hans Clevers: Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center
Bon-Kyoung Koo: Institute for Basic Science
Josef M. Penninger: Vienna BioCenter (VBC)

Nature, 2025, vol. 637, issue 8044, 156-166

Abstract: Abstract 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 Apcmin-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.

Date: 2025
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DOI: 10.1038/s41586-024-08284-1

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