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Porcine Sertoli Cell-Derived Exosomes Drive Spermatogonial Stem Cell differentiation through PSMD11-p38 MAPK-Mediated Redox Signaling

ABSTRACT: Spermatogonial stem cell fate decisions-self-renewal versus differentiation-are orchestrated by complex intercellular communication within the testicular niche. While paracrine signaling has been extensively characterized, the role of extracellular vesicles, especially in livestock, remains poorly understood. Here we demonstrate that primary porcine Sertoli cell-derived exosomes constitute a previously unrecognized regulatory mechanism controlling SSC differentiation through redox homeostasis. Using an ex vivo porcine testicular culture system that recapitulates the native SSC microenvironment, we show that porcine Sertoli cell exosomes promote SSC differentiation, evidenced by decreased expression of stemness markers (GFRA1, UCHL1) and increased differentiation markers (KIT, STRA8). Proteomic profiling revealed enrichment of antioxidant enzymes (SOD1, SOD2, CAT etc.,) within these exosomes. Mechanistically, PSMD11 was identified as a novel regulatory protein within the exosome to modulate SSC redox balance via the p38 MAPK pathway. The differentiation of porcine SSCs was impaired by PSMD11 knockdown, while was recovered by exogenous PSMD11, confirming its functional significance. These findings establish exosome-mediated redox regulation as a fundamental mechanism governing SSC fate decisions, with implications for understanding male fertility, developing therapeutic strategies for azoospermia, and improving reproductive efficiency in agricultural species.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Sus Scrofa (ncbitaxon:9823)

SUBMITTER: Kang Zou

PROVIDER: MSV000098563 | MassIVE | Sat Jul 19 03:49:00 BST 2025

SECONDARY ACCESSION(S): PXD066323

REPOSITORIES: MassIVE

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Project description:Background: Direct reprogramming of somatic cells into induced neural stem cells (iNSCs) holds strong potential for regenerative medicine, especially in large animal models like pigs, which are crucial for translational and preclinical research. However, the molecular mechanisms driving porcine fibroblast-to-iNSC conversion and subsequent differentiation remain poorly understood at the proteomic level. Methods: To map the proteomic changes during reprogramming and differentiation, we performed unbiased label-free discovery proteomics (nano-LC-MS/MS) and targeted SWATH-MS quantification. Proteomes of porcine tail fibroblasts (PTFs), porcine iNSCs (piNSCs; passage 20), and their neuronal and glial differentiated progeny (piNSCs-NGs; passage 21, after 14 days of neural induction) were compared. Two previously established piNSC lines (VSMUi002-B and VSMUi002-E), generated via Sendai virus-mediated reprogramming, were used as the cellular models. Results: The piNSC lines displayed hallmark NSC morphology and expressed canonical markers (PAX6+, SOX2+, NES+, VIM+, OCT4−). Upon differentiation, they generated neuronal and glial cells expressing TUJ1, MAP2, SYP, TH, and GFAP, confirming their multipotency. A total of 4,094 proteins were identified across the three cell states. Multivariate analysis revealed distinct proteomic signatures separating fibroblasts, iNSCs, and their neuronal/glial progeny. The transition from fibroblast to piNSC was marked by increased expression of STMN1, LIMA1, TKT, and NEFL alongside suppression of ARPC5, ACO2, ETFB, and ALDOB. These shifts indicate profound cytoskeletal remodeling and metabolic reprogramming, reflecting a loss of fibroblast identity and the acquisition of a NSC state. During piNSC-to-piNSCs-NGs differentiation, 19 proteins were consistently upregulated. These included neuronal structural proteins (INA, STMN1), cytoskeletal regulators (PFN1), signaling modulators (MBIP), and proteins involved in lysosomal function (NCOA7), cell adhesion (CDHR2), and calcium signaling (ANXA4). Pathway and network analyses highlighted post-transcriptional regulation—particularly involving RNA processing and the RNA exosome complex (e.g., EXOSC3)—as a key feature of differentiation. Conclusion: This study provides the first comprehensive proteomic map of piNSC reprogramming and differentiation in a large animal model. Our findings uncover critical regulatory proteins and pathways governing cytoskeletal organization, metabolism, and RNA processing, offering valuable insights into neural fate transitions. This resource advances the understanding of neural reprogramming in translational models and supports future regenerative and comparative neuroscience efforts.

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Porcine Sertoli Cell-Derived Exosomes Drive Spermatogonial Stem Cell differentiation through PSMD11-p38 MAPK-Mediated Redox Signaling

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