MSCs-Derived Exosomes and Neuroinflammation, Neurogenesis and Therapy of Traumatic Brain Injury

Abstract

Exosomes are endosomal origin membrane-enclosed small vesicles (30–100 nm) that contain various molecular constituents including proteins, lipids, mRNAs and microRNAs. Accumulating studies demonstrated that exosomes initiated and regulated neuroinflammation, modified neurogenic niches and neurogenesis, and were even of potential significance in treating some neurological diseases. These tiny extracellular vesicles (EVs) can derive from some kinds of multipotent cells such as mesenchymal stem cells (MSCs) that have been confirmed to be a potentially promising therapy for traumatic brain injury (TBI) in experimental models and in preclinical studies. Nevertheless, subsequent studies demonstrated that the predominant mechanisms of MSCs’s contributions to brain tissue repairment and functional recovery after TBI were not the cell replacement effects but likely the secretion-based paracrine effects produced by EVs such as MSCs-derived exosomes. These nanosized exosomes derived from MSCs cannot proliferate, are easier to preserve and transfer and have lower immunogenicity, compared with transplanted exogenous MSCs. These reports revealed that MSCs-derived exosomes might promise to be a new and valuable therapeutic strategy for TBI than MSCs themselves. However, the concrete mechanisms involved in the positive effects induced by MSCs-derived exosomes in TBI are still ambiguous. In this review, we intend to explore the potential effects of MSCs-derived exosomes on neuroinflammation and neurogenesis in TBI and, especially, on therapy.

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…MSCs have shown promise in the field of regenerative medicine, since exogenously administered MSCs target injured tissue, interact with brain parenchymal cells, and promote neurorestoration and recovery of neurological function after brain injuries [178,191,204,205]. Despite the differentiation capacity of MSCs, the principal mechanism of their therapeutic action seems to be a robust paracrine capacity, related to their soluble factors as well as generation and release of microvesicles and exosomes [178,205].…”

“…Overall, it has been widely accepted that the exosome secretion is an efficient adaptive mechanism since environmental challenges (such as stress conditions) can influence its composition, biogenesis, and secretion [204,205,225]. In fact, through preconditioning or genetic manipulation of neural cells, their exosome secretion profile can be modified [205,215].…”

“…Via exosomes, MSCs transfer their therapeutic factors, especially miRNAs, to recipient cells, and thereby modify gene expression [205,208]. Although all exosomes contain the constitutive array of proteins, lipids, and RNAs, their contents vary in accordance with the cellular origin and the physiological or pathological condition of the cell and of its extracellular environment [204]. Most of the studies have demonstrated that MSC-derived exosomes contain various miRNAs, which participate in the cell-cell communication and alter the fate of recipient cells [204,223,224].…”

“…Previous studies indicated that MSCs promised to be an effective therapy for brain injury in TBI [175-177, 215, 231-236]. Instead of brain remodeling and functional recovery by cell replacement effects, evidence suggests that the major effects of neurorestoration were due to the paracrine effects of secretion-based factors such as MSCs-derived exosomes that may reduce neuroinflammation, promote neurogenesis and angiogenesis, rescue pattern separation and spatial learning impairments, and improve functional recovery after TBI in animal models [107,176,178,191,204,205,215,216,[235][236][237]. In addition, as exosomes contain various miRNAs, which play a key role in modifying the phenotype and/or the physiology and modulating the cellular processes of the recipient cell, and miRNAs such as miR-21 could be potential therapeutic targets for interventions after TBI, the combination of miRNAs and MSC-derived exosomes might be a novel approach for the treatment of TBI [238].…”

“…MSC is the most prolific exosome producer among the cell types known to produce exosomes [204,222]. Exosomes contain various molecular constituents including proteins and RNAs from maternal cells.…”