Wang W, Wang B, Yin H. Exosomal miR-181d-5p promotes spinal cord injury repair by driving microglial polarization from M1 to M2 phenotype. World J Stem Cells 2026; 18(7): 119260 [DOI: 10.4252/wjsc.119260]
Corresponding Author of This Article
Hua Yin, Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No. 150 Ximen Road, Linhai District, Taizhou 317600, Zhejiang Province, China. yinhuacaro@126.com
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Cell Biology
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Wang W, Wang B, Yin H. Exosomal miR-181d-5p promotes spinal cord injury repair by driving microglial polarization from M1 to M2 phenotype. World J Stem Cells 2026; 18(7): 119260 [DOI: 10.4252/wjsc.119260]
World J Stem Cells. Jul 26, 2026; 18(7): 119260 Published online Jul 26, 2026. doi: 10.4252/wjsc.119260
Exosomal miR-181d-5p promotes spinal cord injury repair by driving microglial polarization from M1 to M2 phenotype
Wei Wang, Bin Wang, Hua Yin
Wei Wang, Bin Wang, Hua Yin, Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou 317600, Zhejiang Province, China
Co-first authors: Wei Wang and Bin Wang.
Author contributions: Wang W and Wang B contributed equally to this manuscript and are co-first authors. Wang W, Wang B, and Yin H participated in the design, interpretation of the studies and analysis of the data and review of the manuscript; Wang W and Wang B drafted the work and revised it critically for important intellectual content and were responsible for the acquisition, analysis and interpretation of data for the work; Yin H made substantial contributions to the conception or design of the work. All authors read and approved the final manuscript.
Supported by Basic Public Welfare Research Plan of Zhejiang Province, No. LGF21H090015; and Taizhou Science and Technology Plan, No. 20ywa08.
Institutional animal care and use committee statement: This study was approved by the Ethics Committee of Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University (Approval No. EZ-T-2025022B).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Hua Yin, Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No. 150 Ximen Road, Linhai District, Taizhou 317600, Zhejiang Province, China. yinhuacaro@126.com
Received: January 23, 2026 Revised: March 10, 2026 Accepted: May 7, 2026 Published online: July 26, 2026 Processing time: 181 Days and 8.4 Hours
Abstract
BACKGROUND
Spinal cord injury (SCI) is a severe neurological condition characterized by limited treatment options and an unfavorable prognosis. Mesenchymal stem cell (MSC)-derived exosomes constitute a novel cell-free therapeutic modality; however, the underlying mechanisms, particularly the role of microRNAs (miRNAs), remain to be fully elucidated.
AIM
To determine whether MSC-derived exosomes facilitate functional recovery following SCI by regulating microglial polarization through the delivery of miR-181d-5p.
METHODS
In vitro, primary microglia stimulated with lipopolysaccharide were treated with characterized MSC-derived exosomes. Microglial polarization was assessed using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. In vivo, a rat model of SCI was administered exosomes, and functional recovery was evaluated using Basso, Beattie, and Bresnahan scoring, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, and immunofluorescence analysis.
RESULTS
MSC-derived exosomes displayed characteristic morphological features and surface markers. In lipopolysaccharide-activated microglia, exosome treatment resulted in a significant reduction in pro-inflammatory cytokines and an increase in anti-inflammatory factors, reflecting a shift from the M1 to the M2 microglial phenotype. Notably, miR-181d-5p was upregulated in microglia following exosome treatment. Downregulation of miR-181d-5p abolished the exosome-mediated effects on microglial polarization. Mechanistically, miR-181d-5p was identified to directly bind to the 3’ untranslated regions of HMGA2 and HMGB2, thereby repressing their expression. In vivo, administration of MSC-exosomes improved locomotor recovery, reduced inflammatory cytokine levels, and modulated microglial/macrophage polarization, as evidenced by reduced CD86 (M1 marker) and elevated CD206 (M2 marker) expression at the lesion site.
CONCLUSION
MSC-derived exosomes attenuate neuroinflammation and promote functional recovery after SCI by delivering miR-181d-5p, which induces a beneficial microglial M2 polarization through targeting HMGA2 and HMGB2. These findings underscore the therapeutic promise of exosomal miR-181d-5p for SCI repair.
Core Tip: Our work demonstrates that mesenchymal stem cell-exosomes promote recovery after spinal cord injury by delivering miR-181d-5p to microglia, thereby repolarizing them from an M1 to an M2 state. This proposed mechanism provides fresh insight into the therapeutic action of mesenchymal stem cell-exosomes and underscores the translational potential of miR-181d-5p in spinal cord injury treatment strategies.
