RANK drives structured intestinal epithelial expansion during pregnancy

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<sup>min</sup>-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.

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Publication Details

Journal
Nature
Published
2024-12-04
DOI
https://doi.org/10.1038/s41586-024-08284-1
Citations
15
Primary Topic
Digestive system and related health
Type
article
Field-Weighted Citation Impact
8.25

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article

RANK drives structured intestinal epithelial expansion during pregnancy

Asier Ullate‐Agote, Bon‐Kyoung Koo, Hiroshi Takayanagi, Laura Katharina Sievers et al.
15 citations
Nature
Digestive system and related health
8.25
article

RANK drives structured intestinal epithelial expansion during pregnancy

Asier Ullate‐Agote, Bon‐Kyoung Koo, Hiroshi Takayanagi, Laura Katharina Sievers, Lisa C. Osborne, Thomas Lendl, Shane J. F. Cronin, Maren Falk‐Paulsen, Rubina Koglgruber, Maria Novatchkova, Matthias Zilbauer, Dominic Lichtscheidl, Astrid Hagelkrüys, Masahiro Onji, Verena Sigl, Philip Rosenstiel, Tsung‐Pin Pai, Josef Penninger, Hans Clevers, I. Kozieradzki, Jürgen Ruland, Komal Nayak, Amanda Andersson-Rolf, Manolis Pasparakis, Shinichiro Sawa, Natalia A. Carranza García
article en
15 citations

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 Apc<sup>min</sup>-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.

NatureVol. 637(8044)
Roche (Switzerland) (CH), Institute of Molecular Biotechnology (AT), Royal Netherlands Academy of Arts and Sciences (NL), Kyushu University (JP), Austrian Academy of Sciences (AT), University of British Columbia (CA), University of Cologne (DE), Research Institute of Molecular Pathology (AT), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB), Cambridge University Hospitals NHS Foundation Trust (GB), University Medical Center Utrecht (NL), Christian-Albrechts-Universität zu Kiel (DE), Institute for Basic Science (KR), Oncode Institute (NL), Navarre Institute of Health Research (ES), University Hospital Schleswig-Holstein (DE), Helmholtz Centre for Infection Research (DE), Princess Máxima Center (NL), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Vienna Biocenter (AT), The University of Tokyo (JP), Medical University of Vienna (AT), Universidad de Navarra (ES), University of Lübeck (DE)
Medical Research Council
Good health and well-being
Openalex Percentile: Top 2%
Digestive system and related health
8.25
DOIOpen Access PDFOpenAlex
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