Growth of the maternal intestine during pregnancy and lactation [Xenium]

The organs of many female animals grow and are metabolically remodelled by reproduction; this process has been historically overlooked. Using the intestine of mouse mothers, a striking and genetically tractable example of reproductive organ resizing, we find that reproductive intestinal remodelling is anticipatory and distinct from diet- or microbiota-induced intestinal resizing. Reproductive remodelling involves partially irreversible elongation of the intestine and fully reversible growth of its epithelium, which ensues from an expansion of the isthmus progenitors, increased progenitor proliferation and accelerated migration of differentiated cells. Through spatiotemporal analysis of gene expression, we identify induction of the SGLT3a transporter in a subset of enterocytes as one of the earliest reproductive hallmarks within the intestinal epithelium. Electrophysiological and genetic interrogations in vivo and in organoids indicate that SGLT3a does not sustain broad digestive functions or enterocyte health. Instead, SGLT3a detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors and gut epithelial growth during reproduction. Our findings reveal unanticipated molecular, cell and organ specificity to physiological organ remodelling, raising the possibility that organ- and state-specific growth programmes could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth. High resolution spatial transcriptomics Xenium experiment using 300 custom probes. Two runs of two slides were performed. On each slide, whole ileum mouse gut roll samples were profiled from virgin, pregnant (day 7) and lactating mice. This resulted in 4 biological replicates in total for each condition.

诸多雌性动物的器官可随生殖过程发生生长与代谢重塑，该现象长期以来被学界忽视。本研究以母鼠肠道为模型——这是一例显著且易于进行遗传学操作的生殖器官重塑案例——研究发现，生殖性肠道重塑具有预见性，且与饮食或菌群诱导的肠道尺寸改变截然不同。生殖性重塑包含肠道的部分不可逆伸长，以及其上皮的完全可逆性生长；该过程源于肠道峡部祖细胞的扩增、祖细胞增殖水平提升，以及分化细胞迁移速度加快。通过对基因表达进行时空分析，我们鉴定出SGLT3a转运蛋白在部分肠上皮细胞中的诱导表达，是肠道上皮内最早出现的生殖相关特征之一。体内与类器官层面的电生理及遗传学实验表明，SGLT3a并不维持广泛的消化功能或肠上皮细胞健康。与之相反，SGLT3a可通过感知质子与钠离子，从外在层面促进生殖过程中邻近Fgfbp1阳性峡部祖细胞的扩增，以及肠道上皮的生长。本研究揭示了生理器官重塑中此前未被认知的分子、细胞及器官特异性，提示我们可借助器官与状态特异性的生长程序，改善妊娠结局或预防此类生长引发的适应不良后果。本研究采用搭载300条定制探针的高分辨率空间转录组Xenium实验平台，开展了两轮载玻片实验（每轮包含2张载玻片）。每张载玻片上均对未交配、妊娠第7天及泌乳期小鼠的完整回肠肠卷样本完成了测序分析，每个实验条件共计获得4个生物学重复样本。