Mesenchymal stem cell exosomes therapy for the treatment of traumatic brain injury: mechanism, progress, challenges and prospects

Abstract

Traumatic brain injury (TBI) is a heterogeneous disease characterized by brain damage and functional impairment caused by external forces. Under the influence of multiple mechanisms, TBI can cause synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammatory cascade reactions, resulting in a high disability and mortality rate for patients and a heavy burden on families and society. Exosomes are cell-derived vesicles that encapsulate a variety of molecules, including proteins, lipids, mRNAs, and other small biomolecules. Among these, exosomes derived from mesenchymal stem cells (MSCs) have garnered significant attention owing to their therapeutic potential in the nervous system, offering broad clinical applicability. Recent studies have demonstrated that MSC-derived exosome injections in traumatic brain injury models effectively mitigate local inflammatory damage and promote nerve regeneration following injury. Owing to their small size, challenging replication, ease of preservation, and low immunogenicity, MSC exosomes are emerging as a promising therapeutic strategy for traumatic brain injury. This review explores the pathogenesis of traumatic brain injury, the underlying mechanisms of MSC exosome action, and the potential clinical applications of MSC exosomes in the treatment of traumatic brain injury.

Keywords: Mesenchymal stem cell exosome; Research progress; Traumatic brain injury.

Fig. 1

Mechanism of traumatic brain injury-induced brain damage

Fig. 2

Processes of exosome formation and binding to target cells. MSCs mesenchymal stem cells

Fig. 3

Mechanism of exosomes promoting vascular regeneration. Akt protein kinase B, VEGF vascular endothelial growth factor, FGF fibroblast growth factor, miR microRNA

Fig. 4

Mechanism of traumatic brain injury-induced neuroinflammation

Fig. 5

Immunomodulation by exosomes from plasmablast stem cells in traumatic brain injury. MSCs mesenchymal stem cells, MSC-EXO mesenchymal stem cell exosomes, NETs neutrophil extracellular traps, TSG-6 TNF-α stimulates gene/protein 6, PGE-2 prostaglandin E2, TGF-β transforming growth factor-β, IDO Indoleamine 2,3-dioxygenase, HL5-G5 leukocyte antigen-G5, HGF hepatocyte growth factor, MMP-9 matrix metalloproteinase-9, ZO-1 blocking small band protein-1, Occludin tight junction closure protein, VEGFR2 endothelial growth factor receptor 2, MAPK mitogen-activated protein kinase, BDNF brain-derived neurotrophic factor, TIMP3 tissue metalloproteinase inhibitor 3, Jak/Stat5 protein tyrosine kinase/signal transduction and transcription activator 5, IL interleukin, Nrf2 nuclear factor E2 related factor 2, ROS reactive oxygen species, NF-κ B nuclear factor kappa B, Treg cells regulatory T cells

Fig. 6

Immune cell-mediated regulation of vascular regeneration. VEGF vascular endothelial growth factor, FGF fibroblast growth factor, MDSCs myeloid-derived suppressor cells

Fig. 7

Mechanism by which extracellular vesicles reduce traumatic brain injury-induced neuronal apoptosis. BCL2 B-cell lymphoma 2, Akt protein kinase B, BAX BCL2 associated X, CDK1 cyclin-dependent kinase 1, RIPKs receptor interacting protein kinases, MLKL mixed lineage kinase domain-like protein

Fig. 8

Mechanism of traumatic brain injury-induced ferroptosis. GSDMD Gasdermin-D, TBI traumatic brain injury, FLC3 A2 solute carrier family 3 member 2, SLC7 A11 solute carrier family 7a member 11, PUFA polyunsaturated fatty acids, DHA docosahexaenoic acid 22:6n-3, AA arachidonic acid 20:4n-6, ACSL4 Acyl-CoA synthetase long-chain family member 4, LPCAT3 lyso-phosphatidylcholine acyltransferase-3, LOX lysyl oxidase, AdA-PE AdA-containing phosphatidylethanolamines, STEAP3 six-transmembrane epithelial antigen of prostate 3, ROS reactive oxygen species, Fer-1 Ferrostatin-1, GSH glutathione, Lip-1 liproxstatin-1, TfR transferrin receptor, GPX glutathione peroxidase family

Fig. 9

Mechanism of TBI-induced neuronal pyroptosis. DAMPs dangerous molecular patterns, PAMPs pathogen-related molecular patterns, NF-κB nuclear factor kappa B, NLRPs NOD-like receptor protein family, ASC apoptosis-related spot like proteins containing cysteine protease recruitment domains, Caspase-1 cysteine containing aspartic acid protease 1, IL interleukin

Fig. 10

Regulatory mechanism of extracellular vesicles from mesenchymal stem cells on TBI-induced neuronal autophagy. mTORC1 mechanistic target of rapamycin complex 1, ATG anti-thymocyte globulins, AMPK AMP-activated protein kinase, SIRT1 sirtuin 1, PIK phosphatidylinositol (PI) kinase