Amphiregulin orchestrates the paracrine immune-suppressive function of amniotic-derived cells through its interplay with COX-2/PGE2/EP4 axis.

The paracrine crosstalk between amniotic-derived membranes (AMs)/epithelial cells (AECs) and immune cells is pivotal in tissue healing following inflammation. Despite evidence collected to date, gaps in understanding the underlying molecular mechanisms have hindered clinical applications. The present study represents a significant step forward demonstrating that amphiregulin (AREG) orchestrates the native immunomodulatory functions of amniotic derivatives via the COX-2/PGE2/EP4 axis. The results highlight the immunosuppressive efficacy of PGE2-dependent AREG release, dampening PBMCs' activation, and NFAT pathway in Jurkat reporter cells via TGF-β signaling. Moreover, AREG emerges as a key protein mediator by attenuating acute inflammatory response in Tg(lysC:DsRed2) zebrafish larvae. Notably, the interplay of diverse COX-2/PGE2 pathway activators enables AM/AEC to adapt rapidly to external stimuli (LPS and/or stretching) through a responsive positive feedback loop on the AREG/EGFR axis. These findings offer valuable insights for developing innovative cell-free therapies leveraging the potential of amniotic derivatives in immune-mediated diseases and regenerative medicine.