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Peer-reviewedCC BY-NC-NDBioactive Materials

3D culture-derived MSC EV facilitate repair by activating microglial autophagy in spinal cord injury

  • Haifeng Liu1
  • Xiaoke Li2
  • Minhui Li3
  • Jingwei Jiu4
  • Yibo Zhao5
  • Dijun Li6
  • Jing Zhang5
  • Lei Yan7
  • Songyan Li2
  • Ruoqi Li8
  • Guangyuan Du2
  • Jiao Jiao Li9
4 more authors
  • Yanan Du10
  • Wei Liu11
  • Bin Zhao12
  • Bin Wang13
13 affiliations
  1. 1Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China
  2. 2Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
  3. 3Department of Thyroid Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
  4. 4Orthopaedic Sports Medicine Center, Beijing Tsinghua Changgung Hospital, Affiliated Hospital of Tsinghua University, Beijing, 102218, China
  5. 5Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China
  6. 6Sports Medicine Center, Department of Orthopedic Surgery/Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, 610064, China
  7. 7Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
  8. 8Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
  9. 9School of Biomedical Engineering Faculty of Engineering and IT University of Technology Sydney, Sydney, NSW, 2007, Australia
  10. 10Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
  11. 11Beijing CytoNiche Biotechnology Co. Ltd, Beijing, 100000, China; Corresponding author.
  12. 12Department of Orthopedics, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China; Corresponding author.
  13. 13Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Corresponding author.
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Abstract

Spinal cord injury (SCI) is characterized by persistent neuroinflammation, neuronal loss, and limited tissue repair. Extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hUC-MSC-EVs) represent a promising cell-free therapeutic approach, although strategies for improving their bioactivity and regulating their cargo composition remain incompletely defined. Here, a gelatin microcarrier-based three-dimensional (3D) culture system was used to generate hUC-MSC-EVs. Compared with EVs generated under conventional two-dimensional (2D) culture conditions, 3D EVs reduced lesion severity, improved functional recovery, and promoted reparative-like changes in ionized calcium-binding adaptor molecule 1(Iba1)-positive microglia/macrophages in a rat SCI model. Transcriptomic, tandem-reporter, and pharmacological analyses indicated that intact autophagic processing contributes to the reparative-like phenotypic effects of 3D EVs in microglial cells. Comparative microRNA (miRNA) profiling identified miRNA-99a-5p as one of the enriched candidates, and gain- and loss-of-function experiments supported its contribution to autophagy-related and phenotype-associated responses in recipient microglia. The 3D culture condition was accompanied by increased nuclear localization of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), increased expression of Y-box binding protein 1 (YBX1), TEA domain transcription factor 4 (TEAD4) occupancy at selected YBX1 promoter regions, and higher EV-associated miR-99a-5p abundance. RNA immunoprecipitation (RIP) analysis further demonstrated an association between YBX1 and miR-99a-5p. Overall, these findings indicate that 3D culture is associated with EV cargo remodeling and improved therapeutic effects after SCI, while miR-99a-5p represents one functional EV-associated cargo contributing to selected microglial responses.

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Cite

BibTeXRIS
BibTeX
@article{liu2026culturederived,
  title = {{3D culture-derived MSC EV facilitate repair by activating microglial autophagy in spinal cord injury}},
  author = {Haifeng Liu and Xiaoke Li and Minhui Li and Jingwei Jiu and Yibo Zhao and Dijun Li and Jing Zhang and Lei Yan and Songyan Li and Ruoqi Li and Guangyuan Du and Jiao Jiao Li and Yanan Du and Wei Liu and Bin Zhao and Bin Wang},
  journal = {Bioactive Materials},
  year = {2026},
  month = oct,
  doi = {10.1016/j.bioactmat.2026.10.011},
  url = {https://doi.org/10.1016/j.bioactmat.2026.10.011},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - 3D culture-derived MSC EV facilitate repair by activating microglial autophagy in spinal cord injury
AU  - Haifeng Liu
AU  - Xiaoke Li
AU  - Minhui Li
AU  - Jingwei Jiu
AU  - Yibo Zhao
AU  - Dijun Li
AU  - Jing Zhang
AU  - Lei Yan
AU  - Songyan Li
AU  - Ruoqi Li
AU  - Guangyuan Du
AU  - Jiao Jiao Li
AU  - Yanan Du
AU  - Wei Liu
AU  - Bin Zhao
AU  - Bin Wang
PY  - 2026
DA  - 2026/10/23
JO  - Bioactive Materials
DO  - 10.1016/j.bioactmat.2026.10.011
UR  - https://doi.org/10.1016/j.bioactmat.2026.10.011
AB  - Spinal cord injury (SCI) is characterized by persistent neuroinflammation, neuronal loss, and limited tissue repair. Extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hUC-MSC-EVs) represent a promising cell-free therapeutic approach, although strategies for improving their bioactivity and regulating their cargo composition remain incompletely defined. Here, a gelatin microcarrier-based three-dimensional (3D) culture system was used to generate hUC-MSC-EVs. Compared with EVs generated under conventional two-dimensional (2D) culture conditions, 3D EVs reduced lesion severity, improved functional recovery, and promoted reparative-like changes in ionized calcium-binding adaptor molecule 1(Iba1)-positive microglia/macrophages in a rat SCI model. Transcriptomic, tandem-reporter, and pharmacological analyses indicated that intact autophagic processing contributes to the reparative-like phenotypic effects of 3D EVs in microglial cells. Comparative microRNA (miRNA) profiling identified miRNA-99a-5p as one of the enriched candidates, and gain- and loss-of-function experiments supported its contribution to autophagy-related and phenotype-associated responses in recipient microglia. The 3D culture condition was accompanied by increased nuclear localization of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), increased expression of Y-box binding protein 1 (YBX1), TEA domain transcription factor 4 (TEAD4) occupancy at selected YBX1 promoter regions, and higher EV-associated miR-99a-5p abundance. RNA immunoprecipitation (RIP) analysis further demonstrated an association between YBX1 and miR-99a-5p. Overall, these findings indicate that 3D culture is associated with EV cargo remodeling and improved therapeutic effects after SCI, while miR-99a-5p represents one functional EV-associated cargo contributing to selected microglial responses.
SN  - 2452-199X
ER  -