RANK drives structured intestinal epithelial expansion during pregnancy

• 成果类型: Article
• 署名作者: Onji, Masahiro; Sigl, Verena; Lendl, Thomas; Novatchkova, Maria; Ullate-Agote, Asier; Andersson-Rolf, Amanda; Kozieradzki, Ivona; Koglgruber, Rubina; Pai, Tsung-Pin; Lichtscheidl, Dominic; Nayak, Komal; Zilbauer, Matthias; Garcia, Natalia A. Carranza; Sievers, Laura Katharina; Falk-Paulsen, Maren; Cronin, Shane J. F.; Hagelkruys, Astrid; Sawa, Shinichiro; Osborne, Lisa C.; Rosenstiel, Philip; Pasparakis, Manolis; Ruland, Juergen; Takayanagi, Hiroshi; Clevers, Hans; Koo, Bon-Kyoung; Penninger, Josef M.
• 署名单位: Vienna Biocenter (VBC); Institute of Molecular Biotechnology (IMBA); Austrian Academy of Sciences; Medical University of Vienna; Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); University of Navarra; Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; University of British Columbia; University of Cambridge; University of Cambridge; University of British Columbia; University of Kiel; Schleswig Holstein University Hospital; University of Kiel; Schleswig Holstein University Hospital; Kyushu University; University of Cologne; University of Cologne; University of Tokyo; University of Tokyo; Princess Maxima Center; Institute for Basic Science - Korea (IBS); Helmholtz Association; Helmholtz-Center for Infection Research; Roche Holding
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1472
• DOI: 10.1038/s41586-024-08284-1
• 发表日期: 2025-01-02
• 关键词: nf-kappa-b; stem-cells; osteoclast differentiation; osteoprotegerin-ligand; identification; cytokine; iga; lactation; beta

摘要

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-kappa Beta (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.