Growth of the maternal intestine during pregnancy and lactation [Xenium]. 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. Overall design: 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会随生殖过程发生生长与代谢重塑，而这一过程长期以来被学界忽视。本研究以雌性小鼠肠道这一极具代表性且易于遗传学操作的生殖器官尺寸重塑模型为研究对象，发现生殖相关的肠道重塑具有预见性，且与饮食或菌群诱导的肠道尺寸变化存在显著差异。生殖相关肠道重塑包含肠道的部分不可逆伸长，以及上皮组织的完全可逆性生长；该过程源于肠道峡部祖细胞 (isthmus progenitors) 的扩增、祖细胞增殖能力增强，以及分化细胞的迁移加速。通过对基因表达进行时空分析，我们鉴定出肠道上皮内部分肠上皮细胞 (enterocytes) 中SGLT3a转运蛋白的诱导表达，是肠道上皮中最早出现的生殖相关特征之一。体内及类器官 (organoids) 水平的电生理与遗传学检测表明，SGLT3a并不维持广泛的消化功能或肠上皮细胞的健康状态。相反，SGLT3a可通过感知质子与钠离子，在生殖过程中外源性促进邻近Fgfbp1阳性的肠道峡部祖细胞扩增与肠道上皮生长。本研究揭示了生理状态下器官重塑中此前未被认知的分子、细胞及器官特异性，提示可利用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反应。实验整体设计：采用300条定制探针开展高分辨率空间转录组Xenium实验，共完成2轮玻片实验（每轮包含2张玻片）。每张玻片均对未受孕、妊娠第7天及泌乳期小鼠的完整回肠肠卷样本进行转录组图谱分析，最终每个实验条件均获得4个生物学重复样本。