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Exosomal OTULIN from M2 macrophages promotes the recovery of spinal cord injuries via stimulating Wnt/β-catenin pathway-mediated vascular regeneration
Abstract
Vascularization following spinal cord injury (SCI) provides trophic support for rebuilding up and maintaining the homeostasis of neuronal networks, and the promotion of angiogenesis is beneficial for functional recovery after SCI. M2 macrophages have been reported to exhibit powerful pro-angiogenic functions during tissue repair. Exosomes are important paracrine mediators of their parent cells and play critical roles in tissue regeneration. However, the role of M2 macrophage-derived exosomes (M2-Exos) in SCI is still largely unknown. In the present study, we determined that M2-Exos could augment the angiogenic activities of spinal cord microvascular endothelial cells (SCMECs) in vitro. Hydrogel-mediated sustained release of M2-Exos significantly promoted vascular regeneration and functional recovery in mice after SCI. Furthermore, proteomics analysis showed that ubiquitin thioesterase otulin (OTULIN) protein was highly enriched in M2-Exos. Functional assays demonstrated that OTULIN protein was required for the M2-Exos-induced pro-angiogenic effects in SCMECs, as well as positive effects on vascular regeneration, cell proliferation, and functional recovery in the mouse model of SCI. Mechanically, OTULIN from M2-Exos could activate the Wnt/β-catenin signaling by increasing the protein level of β-catenin via inhibiting its ubiquitination and trigger the expression of angiogenesis-related genes that are reported to be the downstream targets of Wnt/β-catenin signaling. Inhibition…
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“sEVs from IL-4 or IL-13-stimulated microglia, also referred to as M2 microglia-derived sEVs (M2-sEVs), demonstrated neuroprotective functions by modulating various cell fates across multiple CNS diseases [19, 20].”
From M2 microglia-derived small extracellular vesicles modulate NSC fate after ischemic stroke via miR-25-3p/miR-93-5p-TGFBR/PTEN/FOXO3 axis (2025) · cites this paper as [20]
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Exosomes combined with biomaterials in the treatment of spinal cord injury
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Metadata
- Authors
- Luo, Z., Peng, W., Xu, Y., Xie, Y., Liu, Y., Lu, H., Cao, Y., & Hu, J.
- ORCID
- Hu, Jianzhong
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 136
- Pages
- 519-532
- ISSN
- 1742-7061
- Cited by
- 96
- References
- 4
- Language
- en
- Funders
- Science and Technology Bureau, Changsha (41965)
- National Natural Science Foundation of China (82030071, 81874004, 81902224)
- Fundamental Research Funds for Central Universities of the Central South University (2020zzts265)
- Central South University
- Natural Science Foundation of Hunan Province (2019JJ50959)
- Xiangya Hospital, Central South University
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- Luo, Z., Peng, W., Xu, Y., Xie, Y., Liu, Y., Lu, H., Cao, Y., & Hu, J. (2021). Exosomal OTULIN from M2 macrophages promotes the recovery of spinal cord injuries via stimulating Wnt/β-catenin pathway-mediated vascular regeneration. Acta Biomaterialia. https://doi.org/10.1016/j.actbio.2021.09.026