MSC-derived exosomes promote recovery from traumatic brain injury via microglia/macrophages in rat

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young individuals worldwide. There is currently no effective clinical treatment for TBI, but mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects. In this study, we performed intracerebroventricular microinjection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-ex) in a weight-drop-induced TBI rat model. We found that hADSC-ex promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis in TBI rats. The therapeutic effects of hADSC-ex were comparable to those of hADSC. Sequential in vivo imaging revealed increasing aggregation of DiR-labeled hADSC-ex in the lesion area. Immunofluorescent staining of coronal brain sections and primary mixed neural cell cultures revealed distinct overlap between CM-DiI-labeled hADSC-ex and microglia/macrophages, indicating that hADSC-ex were mainly taken up by microglia/macrophages. In a lipopolysaccharide-induced inflammatory model, hADSC-ex suppressed microglia/macrophage activation by inhibiting nuclear factor κB and P38 mitogen-activated protein kinase signaling. These data suggest that hADSC-ex specifically enter microglia/macrophages and suppress their activation during brain injury, thereby inhibiting inflammation and facilitating functional recovery. They also offer new insight into the cellular targeting, uptake and migration of hADSC-ex, and provide a theoretical basis for new therapeutic strategies for central nervous system diseases.

Mesenchymal Stem Cells for Neurological Disorders

“…[ 63,64 ] In another study, IC, transplantation of MSC‐derived exosomes in TBI rats prevented microglia proinflammatory activation, thereby alleviating neural injury and facilitating functional recovery after brain insult. [ 65 ] Exosomes isolated from MSCs have also been reported to diminish neurological injury in TBI's large animal model. Williams and co‐workers demonstrated that exosomes derived from human BM‐MSCs infused IV in swine subjected to severe TBI improved BBB integrity, decreased brain swelling, and lesion site.…”

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development

“…Mesenchymal stem cells (MSCs) are multipotent stromal cells sourced from bone marrow, adipose tissues, placenta, or umbilical cord ( Table 2 ). Their regenerative capacities underlie their importance in immune modulation [ 106 , 119 , 120 , 121 , 122 ]. The immunomodulatory effects of MSC-derived exosomes on peripheral blood mononuclear cells (PBMCs) have been well established.…”

“…Furthermore, an increase in the regulatory T-cells (Tregs) was also observed in the interaction between Th-cells and exosomes. Together, studies have revealed that MSC-derived exosomes have favorable immunomodulatory properties [ 106 , 120 , 121 , 122 , 123 , 124 , 125 , 126 ], and thus, they are considered as potential therapeutic candidates in many pathological contexts and as a convenient means of delivering therapeutics, enzymes, and genes to targeted cells [ 127 ]. Interestingly, recent evidence suggests that MSC-derived exosomes offer a potentially safe means of treating graft-versus-host disease (GvHD) [ 128 ].…”

HIV Neuroinflammation: The Role of Exosomes in Cell Signaling, Prognostic and Diagnostic Biomarkers and Drug Delivery

“…They also readily diffuse across plasma membranes ( Chen et al, 2016 ; Matsumoto et al, 2017 ). Multiple studies have used exosomes to deliver therapeutics to the brain for multiple conditions such as stroke ( Li et al, 2020 ; Venkat et al, 2020 ), and traumatic brain injury ( Chen et al, 2020 ). Using a zebrafish model, Yang et al (2015) show that exosomes deliver paclitaxel and doxorubicin (cancer therapeutics) across the BBB.…”