Exosomes Derived From Bone Mesenchymal Stem Cells Ameliorate Early Inflammatory Responses Following Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. Although treatment guidelines have been developed, no best treatment option or medicine for this condition exists. Recently, mesenchymal stem cells (MSCs)-derived exosomes have shown lots of promise for the treatment of brain disorders, with some results highlighting the neuroprotective effects through neurogenesis and angiogenesis after TBI. However, studies focusing on the role of exosomes in the early stages of neuroinflammation post-TBI are not sufficient. In this study, we investigated the role of bone mesenchymal stem cells (BMSCs)-exosomes in attenuating neuroinflammation at an early stage post-TBI and explored the potential regulatory neuroprotective mechanism. We administered 30 μg protein of BMSCs-exosomes or an equal volume of phosphate-buffered saline (PBS) via the retro-orbital route into C57BL/6 male mice 15 min after controlled cortical impact (CCI)-induced TBI. The results showed that the administration of BMSCs-exosomes reduced the lesion size and improved the neurobehavioral performance assessed by modified Neurological Severity Score (mNSS) and rotarod test. In addition, BMSCs-exosomes inhibited the expression of proapoptosis protein Bcl-2-associated X protein (BAX) and proinflammation cytokines, tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, while enhancing the expression of the anti-apoptosis protein B-cell lymphoma 2 (BCL-2). Furthermore, BMSCs-exosomes modulated microglia/macrophage polarization by downregulating the expression of inducible nitric oxide synthase (INOS) and upregulating the expression of clusters of differentiation 206 (CD206) and arginase-1 (Arg1). In summary, our result shows that BMSCs-exosomes serve a neuroprotective function by inhibiting early neuroinflammation in TBI mice through modulating the polarization of microglia/macrophages. Further research into this may serve as a potential therapeutic strategy for the future treatment of TBI.

Role of Exosomes in Cancer-Related Cognitive Impairment

“…Xin et al reported that miR-17-92 cluster-enriched exosomes could activate the PI3K/Akt/mTOR/GSK-3β signaling pathway and enhance neural plasticity and functional recovery in rodents with stroke [58]. Several authors [59][60][61][62] have also reported the impact of mesenchymal stem cell (MSC) exosomes on functional outcomes (e.g., cognitive and sensorimotor functions) in rodents with traumatic brain injury (TBI). MSC exosomes administered into rodent models of TBI revealed reduced cortical lesions, attenuated cellular apoptosis, and modulated neuroinflammation [59,60].…”

Mesenchymal stromal cell secretome as a therapeutic strategy for traumatic brain injury

“…Exosomes derived from human bone marrow MSCs have also been reported to attenuate neurological injury and promote functional recovery in the swine model of combined TBI and hemorrhagic shock . Furthermore, treatment of controlled cortical impact‐induced TBI mice with bone marrow MSC exosomes reduced the lesion size and promote neurobehavioral performance . In their study, exosomes inhibit neuroinflammation by modulating the polarization of microglia/macrophages.…”

“…83 Furthermore, treatment of controlled cortical impact-induced TBI mice with bone marrow MSC exosomes reduced the lesion size and promote neurobehavioral performance. 84 In their study, exosomes inhibit neuroinflammation by modulating the polarization of microglia/macrophages. The observed effect was mediated through downregulation of inducible nitric oxide synthase and increase expression of clusters of differentiation 206 and arginase-1.…”

“…In their study, exosomes inhibit neuroinflammation by modulating the polarization of microglia/macrophages. The observed effect was mediated through downregulation of inducible nitric oxide synthase and increase expression of clusters of differentiation 206 and arginase‐1 …”

“…The observed effect was mediated through downregulation of inducible nitric oxide synthase and increase expression of clusters of differentiation 206 and arginase-1. 84 Furthermore, SHED-derived exosomes mitigate neuroinflammation by modulating M1/M2 microglia polarization, promote motor functional recovery, and reduce cortical lesion in a rat model of TBI. 85 Similarly, Kim et al 86 demonstrated that administration of MSC extracellular vesicles reduced inflammation and ameliorates cognitive impairments after TBI in mice.…”