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Abstract <p>Spinal cord injury (SCI) is a kind of central nervous system damage that causes significant disability. Although bone marrow stromal cells (BMSCs) have been shown to be an effective therapy for SCI, the regulation mechanism of BMSCs in SCI is unclear. The SCI models were established by oxygen–glucose deprivation/reoxygenation (OGD/R) treatment and laminectomy operation. Exosomes were isolated from the supernatant of BMSC cultures via differential ultracentrifugation, followed by characterization using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and Western blotting. HE and Nissl staining examined pathological changes and neuronal loss in the spinal cord tissues. MTT and PI staining determined cell viability and death. Lipid ROS, iron, GSH, and MDA levels were detected by the C11-BODIPY 581/591 probe and commercial kits. The interactions between p-STAT3 and the TFRC/DMT1 promoter were analyzed by ChIP and dual luciferase reporter gene assay. BMSCs-derived exosomes (BMSCs-exo) suppressed OGD/R-induced neuronal ferroptosis. AKAP12 knockdown weakened the inhibitory impact of BMSCs-exo on OGD/R-induced neuronal ferroptosis. BMSCs-derived exosomal AKAP12 reduced p-ERK and p-STAT3 levels in neuronal cells and p-STAT3 nuclear entry. Additionally, p-STAT3 entering the nucleus increased TFRC and DMT1 promoter transcriptional activity by binding to their promoters. BMSCs-derived exosomal AKAP12 inhibited lipid peroxidation and iron transport signals by inactivating ERK and STAT3 signaling pathways. BMSCs-exo improved the motor function and injury repair in SCI rats by carrying AKAP12. Taken together,&#xa0;BMSCs-derived exosomal AKAP12 inhibited neuronal ferroptosis by repressing TFRC- and DMT1-mediated iron transport signals through inactivating STAT3 and ERK signaling pathways, thereby mitigating SCI.</p> Key messages <p><UnorderedList Mark="Bullet"> <ItemContent> <p>BMSCs-exo inhibited OGD/R-induced neuronal ferroptosis.</p> </ItemContent> <ItemContent> <p>AKAP12 silencing in BMSCs weakened the inhibitory impact of BMSCs-exo on OGD/R-induced neuronal ferroptosis.</p> </ItemContent> <ItemContent> <p>BMSCs-derived exosomal AKAP12 alleviated OGD/R-induced neuronal ferroptosis by inactivating the STAT3 and ERK pathways.</p> </ItemContent> <ItemContent> <p>Exosomal AKAP12 improved the motor function and injury repair by suppressing the STAT3 and ERK pathways in SCI rats.</p> </ItemContent> </UnorderedList></p>

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BMSCs-derived exosomal AKAP12 alleviates neuronal cell ferroptosis by inhibiting the STAT3 and ERK signaling pathways in spinal cord injury

  • 期刊论文

  • 发表日期：

    2025年10月15日

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  • Fan Wang,
  • Zhigang Pan,
  • Hanlin Zheng,
  • Qiangbin Zhu,
  • Chuhan Ke,
  • Feng Zheng,
  • Weipeng Hu

摘要

Abstract

Spinal cord injury (SCI) is a kind of central nervous system damage that causes significant disability. Although bone marrow stromal cells (BMSCs) have been shown to be an effective therapy for SCI, the regulation mechanism of BMSCs in SCI is unclear. The SCI models were established by oxygen–glucose deprivation/reoxygenation (OGD/R) treatment and laminectomy operation. Exosomes were isolated from the supernatant of BMSC cultures via differential ultracentrifugation, followed by characterization using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and Western blotting. HE and Nissl staining examined pathological changes and neuronal loss in the spinal cord tissues. MTT and PI staining determined cell viability and death. Lipid ROS, iron, GSH, and MDA levels were detected by the C11-BODIPY 581/591 probe and commercial kits. The interactions between p-STAT3 and the TFRC/DMT1 promoter were analyzed by ChIP and dual luciferase reporter gene assay. BMSCs-derived exosomes (BMSCs-exo) suppressed OGD/R-induced neuronal ferroptosis. AKAP12 knockdown weakened the inhibitory impact of BMSCs-exo on OGD/R-induced neuronal ferroptosis. BMSCs-derived exosomal AKAP12 reduced p-ERK and p-STAT3 levels in neuronal cells and p-STAT3 nuclear entry. Additionally, p-STAT3 entering the nucleus increased TFRC and DMT1 promoter transcriptional activity by binding to their promoters. BMSCs-derived exosomal AKAP12 inhibited lipid peroxidation and iron transport signals by inactivating ERK and STAT3 signaling pathways. BMSCs-exo improved the motor function and injury repair in SCI rats by carrying AKAP12. Taken together, BMSCs-derived exosomal AKAP12 inhibited neuronal ferroptosis by repressing TFRC- and DMT1-mediated iron transport signals through inactivating STAT3 and ERK signaling pathways, thereby mitigating SCI.

Key messages

BMSCs-exo inhibited OGD/R-induced neuronal ferroptosis.

AKAP12 silencing in BMSCs weakened the inhibitory impact of BMSCs-exo on OGD/R-induced neuronal ferroptosis.

BMSCs-derived exosomal AKAP12 alleviated OGD/R-induced neuronal ferroptosis by inactivating the STAT3 and ERK pathways.

Exosomal AKAP12 improved the motor function and injury repair by suppressing the STAT3 and ERK pathways in SCI rats.