Pregnancy induces intestinal epithelial elongation and estriol-associated activation of the Hippo signaling pathway in a mouse model.

During pregnancy and weaning, the intestinal tract undergoes adaptations on different levels, including altered immune cell frequencies and epithelial changes. We could show in a mouse model that the overall area (crypt-villus axis length and total length) of the small intestine increased during this period of higher maternal nutrient need and that the increased area correlated with maternal weight. Quantification of cell proliferation and cell death showed an increased proliferation of epithelial cells in the lower and middle crypt. In cell culture, estriol maintained epithelial cell proliferation and progesterone-inhibited proliferation. Further, Hippo signaling is a well-known pro-proliferative pathway which integrates several upstream signals and ultimately leads to nuclear translocation of the transcription factor YAP. In the small intestine, YAP is expressed in epithelial cells, immune cells, and fibroblasts. During pregnancy and weaning, epithelial and stroma cells exhibit strong nuclear staining of YAP. Interestingly, estriol led to upregulation and increased nuclear shuttling of YAP in intestinal epithelial cell monolayers. This effect appears to be specific to the estriol treatment since the established pro-proliferative cytokine GLP-2 did not lead to increased nuclear shuttling of YAP.