Int J Stem Cells.  2024 Aug;17(3):236-252. 10.15283/ijsc23092.

The Role of Exosomes from Mesenchymal Stem Cells in Spinal Cord Injury: A Systematic Review

• Wang H
• Zhao C
• Rong Q
• Cao J
• Chen H
• Li R
• Zhang B
• Xu P

• KMID: 2558603
• DOI: http://doi.org/10.15283/ijsc23092

Abstract

Spinal cord injury (SCI) is a serious nervous system disease that usually leads to the impairment of the motor, sensory, and autonomic nervous functions of the spinal cord, and it places a heavy burden on families and healthcare systems every year. Due to the complex pathophysiological mechanism of SCI and the poor ability of neurons to regenerate, the current treatment scheme has very limited effects on the recovery of spinal cord function. In addition, due to their unique advantages, exosomes can be used as carriers for cargo transport. In recent years, some studies have confirmed that treatment with mesenchymal stem cells (MSCs) can promote the recovery of SCI nerve function. The therapeutic effect of MSCs is mainly related to exosomes secreted by MSCs, and exosomes may have great potential in SCI therapy. In this review, we summarized the repair mechanism of mesenchymal stem cells-derived exosomes (MSCs-Exos) in SCI treatment and discussed the microRNAs related to SCI treatment based on MSCs-Exos and their mechanism of action, which is helpful to further understand the role of exosomes in SCI.

Keyword

Spinal cord injury; Mesenchymal stem cells; Exosomes; miRNA; Delivery vehicles

Figure

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  Fig. 1 Pathophysiology of spinal cord injury (SCI). BSCB: blood-spinal cord barrier.

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  Fig. 2 Exosome formation, secretion, and action on target cells. Formation of mesenchymal stem cells-derived exosomes (MSCs-Exos): ① Endocytosis: The extracellular component and cell surface protein are engulfed into the cells through the invagination of the plasma membrane to form an early endosome (EE); ② First exchange: The EE could initially exchange goods with the Golgi network and endoplasmic reticulum to form the late endosome (LE); ③ Secondary exchange: LE conducts cargo exchange again through the second plasma membrane invagination and finally forms intraluminal vesicles (ILVs), and the collection of multiple ILVs of different sizes is called a multivesicular body (MVB); ④ Plasma membrane budding: Some MVBs release exosomes extracellularly through plasma membrane budding; ⑤ Recycling: Some MVBs can be degraded by lysosomal fusion, and the degradation products can be recovered by cells. The structure of MSCs-Exos: Exosomes express tetraspanins (CD81, CD63, and CD9), heat shock proteins (HSP60, HSP70, and HSP90), ALG-2 interacting protein X (Alix), TSG101, integrins, flotillin, surface markers (CD44, CD73, and CD90) and adhesion molecules (CD29, CD44, and CD73). In addition, MSCs-Exos carry nucleic acids, proteins, and enzymes. Exosomes enter recipient cells in three ways: ⑥ receptor-mediated entry, ⑦ direct membrane fusion, and ⑧ endocytosis.

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  Fig. 3 The mechanism by which mesenchymal stem cells-derived exosomes (MSCs-Exos) regulate the immune response. Bone marrow stem cell (BMSC)-Exos can regulate the TLR4/MyD88/NF-κB signaling pathway to produce the production of anti-inflammatory factors. MSCs-Exos with miR-181c and miR-23b can inhibit the formation of microglia via the Phosphatase and Tensin homolog (PTEN) signaling pathway and inhibit the TLR4/NF-κB pathway to inhibit the production of proinflammatory factors. Epidural fat (EF)-MSCs-Exos and human Wharton’s jelly (HWJ)-MSCs-Exos can inhibit the NLRP3 activation to inhibit the production of proinflammatory factors. MSCs-Exos with miR-125a and miR-124-3p can inhibit M2 macrophage polarization by regulating the IRF5 and Ern1 signaling pathways. MSCs-Exos with miR-216a-5p can inhibit M2 macrophage polarization by inhibiting TLR4/NF-κB and activating the PI3K/Akt signaling pathway. MSCs-Exos can inhibit the NFκB p65 signaling pathway to reduce astrocyte toxicity. MSCs-Exos with miR-146a-5p can inhibit the Traf6/Irak1/NF-κB signaling pathway to reduce astrocyte toxicity.

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  Fig. 4 The mechanism by which mesenchymal stem cells-derived exosomes (MSCs-Exos) promotes angiogenesis and regulates blood-spinal cord barrier (BSCB) integrity. MSCs-Exos can promote angiogenesis by promoting the expression of vascular endothelial growth factor (VEGF) via the PKA signaling pathway. BMSC-Exos can suppress pericyte pyroptosis and inhibit pericyte migration by activating the NF-κB signaling pathway to maintain BSCB integrity. MSCs-Exos could increase the expression of cell junction proteins via the TIMP2/MMP pathway to attenuate the destruction of the BSCB. MSCs-Exos could reduce BSCB permeability by targeting M2 macrophages to upregulate TGFβ and TGFβ receptor expression.

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  Fig. 5 The mechanism by which mesenchymal stem cells-derived exosomes (MSCs-Exos) regulates apoptosis and autophagy. Bone marrow stem cell (BMSC)-Exos can inhibit apoptosis by regulating the Wnt/β-catenin signaling pathway. human umbilical cord (HUC)-MSCs-Exos can regulate the Wnt/β-catenin signaling pathway and the Bcl-2/Bax axis to inhibit apoptosis. MSCs-Exos with miR-19b and miR-181c can inhibit apoptosis via the Phosphatase and Tensin homolog (PTEN) signaling pathways. MSCs-Exos with miR-21 can inhibit apoptosis via the PTEN and PDCD4 signaling pathways. MSCs-Exos with miR-21-5p and miR-29b-3p can inhibit apoptosis by regulating the FasL signaling pathway and activating the Akt/mTOR signaling pathway. MSCs-Exos with miR-381 can inhibit apoptosis via BRD4/WNT5A signaling pathways. MSCs-Exos with miR-499-5p inhibits the JNK3/MAPK10 and JNK3/c-jun signaling pathways to inhibit apoptosis. MSCs-Exos with miR-9-5p and miR-511-3P could regulate the HDAC5/FGF2 and TRAF6/S1P signaling pathways to inhibit apoptosis. MSCs-Exos could regulate the autophagy-related proteins LC3IIB and Beclin-1 to promote autophagy.

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  Fig. 6 The mechanism by which mesenchymal stem cells-derived exosomes (MSCs-Exos) promotes axonal growth and neuronal regeneration. MSCs-Exos can promote axonal growth by promoting M2 macrophage polarization by inhibiting the NF-κb/NLRP3 signaling pathway. MSCs-Exos with miR-199a-3p/145-5p can target Cblb/Cbl mRNAs to inhibit the NGF/TrkA pathway to promote axonal growth. Human placenta (HP)-MSCs-Exos can promote neuronal regeneration by activating the MEK/ERK/CREB signaling pathway. MSCs-Exos could attenuate R-Smad 6 expression to promote neuronal regeneration by carrying TGFβ. MSCs-Exos with miR-let-7a-5p downregulated SMAD2 expression by inhibiting HMGA2 to promote neuronal regeneration.

Reference

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