奥地利科学院分子生物技术研究所Penninger Josef M.研究小组报道，RANK驱动妊娠期肠道上皮结构扩张。这一研究成果发表在2024年12月4日出版的国际学术期刊《自然》上。

研究人员表示，在繁殖过程中，许多物种（如昆虫和所有哺乳动物）都经历了广泛的生理和形态适应，以确保母亲的健康和生存以及后代的最佳发育。

研究人员人员报道了哺乳动物在怀孕和哺乳期间肠上皮的扩张。这种肠表面积的扩大导致肠绒毛扩张的新几何形状。核因子受体激活因子-κΒ （Receptor activator of nuclear factor-κΒ， RANK，由TNFRSF11A编码）及其配体RANKL被鉴定为参与小鼠体内小肠绒毛扩张的分子途径，并参与肠母细胞和人类器官的扩张。

在机制上，RANK-RANKL保护肠道上皮细胞免于细胞死亡，并通过BMP受体信号传导控制肠道干细胞生态位，导致绒毛伸长和肠表面显著增加。作为跨代后果，肠道上皮缺乏Rank的雌性小鼠所生的婴儿在代谢应激后体重减轻并出现葡萄糖耐受不良。

尽管妊娠/哺乳期肠道上皮重塑是可逆的，但活性形式RANK的组成性表达足以驱动肠道扩张，随后绒毛和干细胞的丢失，并阻止apcmin驱动的小肠干细胞肿瘤的形成。这些数据确定RANK-RANKL是妊娠/哺乳期间肠上皮扩张的途径，这是哺乳动物生活史和进化中最重要和最基本的组织重塑事件之一。

附：英文原文

Title: RANK drives structured intestinal epithelial expansion during pregnancy

Author: 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, Carranza Garca, Natalia A., Sievers, Laura Katharina, Falk-Paulsen, Maren, Cronin, Shane J. F., Hagelkruys, Astrid, Sawa, Shinichiro, Osborne, Lisa C., Rosenstiel, Philip, Pasparakis, Manolis, Ruland, Jrgen, Takayanagi, Hiroshi, Clevers, Hans, Koo, Bon-Kyoung, Penninger, Josef M.

Issue&Volume: 2024-12-04

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.

DOI: 10.1038/s41586-024-08284-1

Source: https://www.nature.com/articles/s41586-024-08284-1