Protective effect of BMSCs-derived exosomes mediated by BDNF on TBI via miR-216a-5p

Abstract

Background: Transplantation of exosomes derived from mesenchymal stem cells (MSCs-Exo) can improve the recovery of neurological function in rats after traumatic brain injury (TBI). We tested a new hypothesis that brain-derived neurotrophic factor (BDNF)-induced MSCs-Exo can effectively promote functional recovery and neurogenesis in rats after TBI. Material/Methods: BM-MSCs of rats were extracted by whole bone marrow culture, BDNF was added to BM-MSCs as an intervention, supernatant was collected, and exosomes were separated and purified by ultracentrifugation. Exosomes were identified by Western blot (WB), transmission electron microscopy (TEM), and particle size analysis and were subsequently used in cell and animal experiments. The experimental animals were divided into a sham group, a PBS group, an MSCs-Exo group, and a BDNF-induced MSCs-Exo group (n=12). An electric cortical contusion impactor (eCCI) was used to cause TBI in all rats except the sham group. We investigated the recovery of sensorimotor function and spatial learning ability, inflammation inhibition, and neuron regeneration in rats after TBI. Results: Compared with the MSCs-Exo group, the BDNF-induced MSCs-Exo group showed better effects in promoting the recovery of sensorimotor function and spatial learning ability. BDNF-induced MSCs-Exo successfully inhibited inflammation and promoted neuronal regeneration in vivo and in vitro. We further analyzed miRNAs in BDNF-induced MSCs-Exo and MSCs-Exo and found that the expression of miR-216a-5p in BDNF-induced MSCs-Exo was significantly higher than that in MSCs-Exo as determined by qRT-PCR. Rescue experiments indicated that miR-216a-5p had a similar function as BDNF-induced MSCs-Exo. Conclusions: We found that BDNF-induced MSCs-Exo can improve cell migration and inhibit apoptosis better than MSCs-Exo in rats after TBI, and the mechanism may be related to the high expression of miR-216a-5p.

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

“…(100). Several studies in TBI demonstrated presence of EV markers using western blot (e.g., CD63, CD9, HSP70) (213,214) and Chen et al (214) utilized western blotting (WB) to show presence of GJA1-20K from astrocyte-derived EVs which facilitated neuronal recovery. MISEV also recommends characterization of EV morphology using transmission electron microscopy and characterization of EV size and concentration, most often conducted using nanoparticle tracking analysis (100).…”

Extracellular vesicles as mediators and markers of acute organ injury: current concepts

“…Furthermore, BMSCs-Exos could modulate microglia/macrophage polarization by downregulating the expression of inducible nitric oxide synthase (INOS) and upregulating the expression of CD206 and arginase-1 [ 79 ]. MSC-derived Exos loaded with neuroprotective miR-216a-5p were shown to inhibit neuroinflammation and promote neuronal regeneration and in particular recovery of sensorimotor function and spatial learning ability [ 80 ]. MSC exosome-treated TBI rats show significant improvement in spatial learning as measured by the modified Morris water maze test and sensorimotor functional recovery [ 81 ].…”

Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes

“…Similarly, MSC-derived exosome loaded with curcumin suppressed cellular apoptosis in the lesion region in a mouse model of stroke [ 102 ]. Moreover, MSC-derived exosomes enriched with BDNF were found to inhibit apoptosis and promote neuronal regeneration in a TBI rat model [ 103 ].…”

“…Direct methods include chemical reactions [ 94 , 99 , 102 , 104 ], electroporation [ 100 ], cholesterol-conjugation (hydrophobic reaction) [ 94 , 98 ], and incubation [ 102 ]. Indirect methods targeting the cells include transfection (via lipofectamine or virus infection) [ 89 , 91 , 92 , 95 , 96 , 97 , 101 ], electroporation [ 106 ], or addition as a media supplement [ 103 , 105 ]. The efficiency of these methods has not yet been compared and, therefore, no information is available regarding the optimal loading method.…”