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Sacral Neural Crest-Derived Extracellular Vesicles Suppress Pyroptosis via the ANXA1-FPR2 Axis to Repair Pelvic Ganglia

ABSTRACT: Pelvic autonomic nerve injury is a major cause of postoperative bowel dysfunction, yet effective strategies for restoring damaged pelvic ganglia remain lacking. Here, we demonstrate that extracellular vesicles derived from human pluripotent stem cell–induced sacral neural crest cells (Sacral NC-EVs) promote pelvic neuroregeneration by suppressing oxidative stress–induced pyroptosis. In a rat model of major pelvic ganglion (MPG) injury, local administration of Sacral NC-EVs improved gastrointestinal motility and partially restored rectal neural innervation and epithelial barrier integrity. Mechanistically, MPG injury induced a hypoxia-associated oxidative microenvironment that activated the NLRP3–caspase-1–GSDMD pyroptosis pathway, whereas Sacral NC-EVs effectively attenuated oxidative stress and inhibited pyroptotic signaling. Comparative analyses showed that Sacral NC-EVs produced more pronounced overall therapeutic effects than mesenchymal stem cell–derived and vagal neural crest–derived EVs, highlighting a functional advantage of developmental lineage matching. Proteomic and functional studies identified annexin A1 (ANXA1) as an important EV-associated mediator that acts through FPR2 signaling to contribute to the antioxidant and anti-pyroptotic effects of Sacral NC-EVs. Collectively, our findings establish lineage-matched EVs as a mechanism-driven, cell-free strategy for neural repair by targeting the oxidative stress–pyroptosis axis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wu Song

PROVIDER: PXD081233 | iProX | Fri Jul 17 00:00:00 BST 2026

REPOSITORIES: iProX

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