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Melatonin Synergizes with Prostaglandin E2 to Enhance YAP-mediated Regenerative Epithelial Cell Emergence During Intestinal Repair

ABSTRACT: In this study, we explore the role of melatonin, abundantly secreted by enteroendocrine cells (EECs) yet overlooked beyond its circadian regulation, in promoting intestinal regeneration. Our findings demonstrate that melatonin can be integrated into the PGE2-EP4-YAP signaling axis to facilitate injury-responsive reprogramming and RSC induction in the intestinal epithelium both in vitro and in vivo. This work uncovers a novel function of melatonin, opening new therapeutic possibilities in regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE293340 | GEO | 2025/03/31

REPOSITORIES: GEO

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Project description:Recognition of foreign antigens by B cell receptor (BCR) on mature B cells leads to their clonal expansion, which is critically important for the effective host defence of the organism. However, excessive antigenic responses or reaction of B cells against bodyâs own components frequently lead to diverse immune diseases, such as B-cell lymphoma or autoimmunity, that often affect humans. Identification of genes that restrain uncontrolled proliferation of B cells is therefore an important goal towards understanding the origin of such diseases. Here we identify Ptger4 as a negative feedback regulator of B-cell proliferation in response to BCR triggering, and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). In controlled in vitro assays, Ptger4-/- B cells showed augmented proliferative response and increased expression of activating genes upon BCR stimulation. Stable knock-down of Ptger4 in B-cell lymphoma markedly accelerated tumour spread in mice, while Ptger4 overexpression yielded significant protection. Lack of Ptger4 rendered mouse B cells completely resistant to proliferation arrest signalled by PGE2, and we find by transcriptional profiling that intrinsic activity of Ptger4 and PGE2-EP4 signalling target a similar set of activating genes. We further show that Ptger4 inhibits mouse B-cell activation in vivo and find it significantly downregulated in human B-cell lymphoma. Our results demonstrate that Ptger4 functions in B cells as a candidate tumour suppressor whose activity is regulated by the presence of PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B-cell diseases. Keywords: time course, cell type comparison, compound treatment design, microarray experiment record B cells were extracted from spleen of Ptger4+/+ and Ptger4-/- mice, and incubated in vitro for the indicated period with or without anti-IgM (Fab')2 antibody fragments and co-treated with or without PGE2. Total RNA was extracted, amplified, labelled with Cy3 or Cy5, and hybridized to mouse 24k oligo-arrays using a dye-swap strategy.

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Melatonin Synergizes with Prostaglandin E2 to Enhance YAP-mediated Regenerative Epithelial Cell Emergence During Intestinal Repair

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