Selenomethionine drives microglial epigenetic remodeling to couple neuromuscular regeneration via Dot1l-H3K79me
Description
Spinal cord injury (SCI) patients frequently present with severe neural damage and muscle atrophy, limiting the recovery of motor function. Microglia are essential for immune microenvironment homeostasis within the central nervous system (CNS), which offers a promising strategy for neuromuscular regeneration following SCI. Herein, integrating single-cell transcriptomics and clinical cohort analyses, we identified that selenium metabolism is involved into development of pro-repairing microglia and correlated with favorable neuromuscular recovery in SCI patients. Furthermore, we developed a temperature-responsive hydrogel for localized selenomethionine delivery named SMART (SelenoMethioninet Autonomous Release Therapy), which remodeled microglial paracrine profile to promote motor recovery, nerve remyelination, and skeletal muscle regeneration in SCI model mice. Mechanistically, SMART-mediated SeAM accumulation enhanced the Dot1l m6A-H3K79me3 epigenetic cascade, thereby facilitating chromatin accessibility for neurotrophic and myogenic factors in microglia. This SeMet-Dot1l-H3K79me3 axis-mediated microlial functional remodeling and nerve and muscle regeneration was validated in SCI mice model and patient cohorts. Our findings established selenomethionine-driven Dot1l m6A modification as a critical epigenetic regulator of microglial paracrine signaling and neuromuscular repair, offering a promising immunometabolic strategy for SCI.