iPS-derived exosomes alleviated pancreatic ischemia reperfusion injury through activating the AMPK/mTOR/NF-κB pathway

Pancreatic ischemia-reperfusion (IR) injury is a key factor contributing to post-transplantation rejection and graft dysfunction. This study investigated the therapeutic potential of exosomes derived from induced pluripotent stem cells (iPS-EXOs), a novel, cell-free therapeutic strategy, in a rat model of pancreatic IR injury induced by splenic artery occlusion. Administration of iPS-EXOs significantly improved survival, attenuated pancreatic edema, and ameliorated histopathological damage. The protective effects were mediated through multi-faceted actions that iPS-EXOs restored microcirculatory perfusion through promoting VEGF-A/VEGFR2 signaling, mitigated oxidative stress via normalizing levels of ROS, MDA, MPO, GPx, and SOD, and suppressed the inflammatory cascade by reducing serum levels of IL-1β, IL-6, and TNF-α. Furthermore, iPS-EXOs exerted anti-apoptotic effects, as evidenced by decreased TUNEL-positive cells and modulation of BCL-2/BAX and Caspase-3/9 pathways. We identified that hsa-miR-1976 in iPS-EXOs could target HRH4, leading to AMPK activation and subsequent inhibition of the mTOR/NF-κB signaling pathway. Collectively, our reuslts demonstrated that iPS-EXOs exerted protection against pancreatic IR injury of rat by coordinating microvascular repair, anti-oxidant, anti-inflammatory, and anti-apoptosis through endogenous hsa-miR-1976 binding to HRH4 to activate AMPK/mTOR/NF-κB pathway. These findings indicated that iPS-EXOs could be a promising therapeutic agent for pancreatic IR injury.