Porcine Sertoli cell exosomes tune the redox setpoint of spermatogonial stem cells through PSMD11–p38 MAPK signaling to mediate differentiation

Spermatogonial stem cell (SSC) fate—the choice between self-renewal and differentiation—is governed by intercellular signaling within the testicular niche. A central paradigm holds that endogenous reactive oxygen species (ROS) sustain SSC self-renewal through MAPK signaling. Yet how the niche actively lowers ROS to permit differentiation, and which intercellular carriers mediate this, remains unknown. The contribution of extracellular vesicles to this redox control, especially in livestock species, is largely uncharacterized. Using an ex vivo porcine testicular culture system that preserves the native porcine SSC (pSSC) niche, together with a feeder-free pSSC culture and quantitative proteomics, we defined the function and molecular cargo of porcine Sertoli cell (pSC)-derived exosomes. pSC-derived exosomes were markedly enriched in antioxidant enzymes, including SOD1, SOD2, GPXs, PRDXs, and CAT, which together lowered intracellular ROS in pSSCs through the SOD-dependent ROS cascade. This redox tuning shifted pSSCs from self-renewal toward differentiation. Mechanistically, we identified PSMD11—a 19S proteasome subunit not previously known as an exosomal cargo or a niche redox regulator—as a key effector. Exosomal PSMD11 reduced pSSC ROS, suppressed p38 MAPK activation, and drove differentiation. Recombinant PSMD11 reproduced the exosomal phenotype, and PSMD11 knockdown produced the opposite effect. Sertoli cells export an antioxidant proteome, spearheaded by PSMD11, that sets the redox tone of neighboring SSCs and thereby licenses differentiation through p38 MAPK. This positions exosome-delivered redox tuning as an active, conserved mechanism of SSC fate control, with implications for treating azoospermia and for improving reproductive efficiency in agriculturally important species.