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Background <p>Spinal cord injury (SCI) leads to persistent neurological deficits partly by disruption of the blood-spinal cord barrier (BSCB). Small extracellular vesicles (sEVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) can promote BSCB repair, but their active components remain unclear. This study examined whether miR-149 carried by hUC-MSC-derived sEVs (hUC-MSCs-sEVs) protects the BSCB after SCI by targeting endothelin-1 (ET-1).</p> Methods <p>Human brain microvascular endothelial cells (HBMECs) were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) to model barrier injury, and rats underwent a thoracic SCI. hUC-MSCs-sEVs were isolated and loaded with miR-149 mimics or inhibitors. Endothelial cell viability, paracellular permeability (FITC-dextran assay), and junction protein levels (ZO-1, Claudin-5, β-Catenin, Occludin) were measured by viability assays, Western blot, and immunofluorescence. ET-1 levels and PI3K/Akt pathway activation were measured by ELISA and Western blot. In SCI rats, sEVs (with or without the miR-149 inhibitor) were injected; motor function (BBB locomotor score), BSCB permeability (Evans blue/FITC-dextran leakage) and spinal cord histology were evaluated.</p> Results <p>hUC-MSCs-sEVs were internalized by HBMECs and significantly improved cell survival and barrier function after OGD/R. sEVs treatment restored tight and adherens junction proteins and suppressed OGD/R-induced ET-1 upregulation and PI3K/Akt activation. OGD/R reduced miR-149 expression, which was rescued by sEVs. sEVs loaded with miR-149 mimic further enhanced these protective effects, whereas a miR-149 inhibitor abolished them. Notably, co-administration of an ET-1 receptor antagonist reversed the barrier disruption caused by miR-149 inhibition. In vivo, hUC-MSCs-sEVs treatment improved locomotor recovery and reduced BSCB leakage and tissue damage, whereas miR-149 inhibition abolished these benefits.</p> Conclusions <p>hUC-MSC-derived exosomal miR-149 preserves BSCB integrity and promotes functional recovery after SCI by targeting ET-1 and inhibiting the PI3K/Akt pathway, thereby enhancing junctional protein expression. The miR-149/ET-1 axis may represent a promising therapeutic target for SCI.</p> Graphical Abstract <p></p>

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Exosomal miR-149 from human umbilical cord mesenchymal stem cells attenuates spinal cord injury-induced blood-spinal cord barrier disruption by suppressing the ET-1/PI3K/Akt signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Chenhui Xue,
  • Xiaochen Qiao,
  • Wenxuan Wang,
  • Zhenwu Gao,
  • Xin Chen,
  • Xihua Yang,
  • Hui Wang,
  • Jiansheng Jing,
  • Haoyu Feng,
  • Hui Zhang,
  • Lin Sun,
  • Xiaoming Guan

摘要

Background

Spinal cord injury (SCI) leads to persistent neurological deficits partly by disruption of the blood-spinal cord barrier (BSCB). Small extracellular vesicles (sEVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) can promote BSCB repair, but their active components remain unclear. This study examined whether miR-149 carried by hUC-MSC-derived sEVs (hUC-MSCs-sEVs) protects the BSCB after SCI by targeting endothelin-1 (ET-1).

Methods

Human brain microvascular endothelial cells (HBMECs) were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) to model barrier injury, and rats underwent a thoracic SCI. hUC-MSCs-sEVs were isolated and loaded with miR-149 mimics or inhibitors. Endothelial cell viability, paracellular permeability (FITC-dextran assay), and junction protein levels (ZO-1, Claudin-5, β-Catenin, Occludin) were measured by viability assays, Western blot, and immunofluorescence. ET-1 levels and PI3K/Akt pathway activation were measured by ELISA and Western blot. In SCI rats, sEVs (with or without the miR-149 inhibitor) were injected; motor function (BBB locomotor score), BSCB permeability (Evans blue/FITC-dextran leakage) and spinal cord histology were evaluated.

Results

hUC-MSCs-sEVs were internalized by HBMECs and significantly improved cell survival and barrier function after OGD/R. sEVs treatment restored tight and adherens junction proteins and suppressed OGD/R-induced ET-1 upregulation and PI3K/Akt activation. OGD/R reduced miR-149 expression, which was rescued by sEVs. sEVs loaded with miR-149 mimic further enhanced these protective effects, whereas a miR-149 inhibitor abolished them. Notably, co-administration of an ET-1 receptor antagonist reversed the barrier disruption caused by miR-149 inhibition. In vivo, hUC-MSCs-sEVs treatment improved locomotor recovery and reduced BSCB leakage and tissue damage, whereas miR-149 inhibition abolished these benefits.

Conclusions

hUC-MSC-derived exosomal miR-149 preserves BSCB integrity and promotes functional recovery after SCI by targeting ET-1 and inhibiting the PI3K/Akt pathway, thereby enhancing junctional protein expression. The miR-149/ET-1 axis may represent a promising therapeutic target for SCI.

Graphical Abstract