Seminiferous tubule–inspired coaxial bioprinting–derived extracellular vesicles restore Leydig cell steroidogenesis through modulation of Wnt4/β-catenin signaling

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Abstract Chemotherapy-associated gonadotoxicity compromises Leydig cell steroidogenesis and leads to testosterone deficiency, yet repair is hindered by the testicular barrier–immune niche and by limited manufacturability of biologics. Inspired by the tubular architecture of seminiferous tubules, we develop a coaxial bioprinting–enabled encapsulation culture that generates continuous core–shell hydrogel microfibers for high-density 3D culture of human umbilical cord MSCs (hUMSCs) and continuous conditioned-medium harvesting, producing seminiferous tubule–inspired coaxial bioprinting–derived extracellular vesicles (STi-EVs). We directly benchmark STi-EVs against conventional 2D culture–derived EVs (2D-EVs) in a 4-hydroperoxycyclophosphamide (4-HC)–injured TM3 model and a cyclophosphamide-induced mouse model. Across cellular fitness, re-engagement of steroidogenic programs, and testosterone output, STi-EVs consistently outperform 2D-EVs, while more effectively alleviating testicular histopathology and restoring serum testosterone in vivo. Transcriptomics prioritize Wnt signaling and nominate Wnt4; orthogonal validation and Wnt4 gain- and loss-of-function perturbations, and β-catenin stabilization experiments support that modulation of Wnt4/β-catenin signaling functionally contributes to STi-EV-mediated steroidogenic restoration. Collectively, this work couples a scalable extracellular vesicles (EV) manufacturing paradigm with a mechanism-informed repair strategy for endocrine sequelae after alkylating chemotherapy. Graphical Abstract

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