Oxytocin regulation of intestinal stem cell self-renewal and differentiation

The intestinal mucosa undergoes a tightly regulated process of proliferation and differentiation, essential for maintaining gut homeostasis. We have previously demonstrated that oxytocin (OXT), a novel gastrointestinal (GI) hormone, plays a crucial role in regulating intestinal injury. However, its functional significance in intestinal epithelial cells (IECs) remains largely uncharacterized. In this study, we demonstrate that the OXT/OXTR signaling axis enhanced proliferation and differentiation of IECs in mouse small intestinal organoids. Pharmacological inhibition or genetic knockout (KO) of OXTR in IECs leads to impaired intestinal stem cell self-renewal, reduced Paneth cell abundance, and exacerbated 5-fluorouracil (5-FU)-induced mucositis. Mechanistically, OXT stimulates prostaglandin E2 (PGE2) production via upregulation of prostaglandin-endoperoxide synthases (COX-1/COX-2), and activates the PGE2 receptor EP4. Notably, the OXT-driven effects are abrogated by COX or EP4 inhibition. Furthermore, OXT signaling enhances YAP activation through a PGE2/EP4-dependent mechanism, linking the OXT/PGE2/EP4 axis to modulation of the Hippo pathway. Our findings establish that OXT orchestrates intestinal epithelial regeneration by promoting stem cell self-renewal via the PGE2/EP4/Hippo/YAP signaling cascade. These results highlight the therapeutic potential of OXT in mitigating chemotherapy-induced intestinal injury.