Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway

Abstract

Spinal cord injury (SCI) is one of the most common destructive injuries, which may lead to permanent neurological dysfunction. Currently, transplantation of bone marrow mesenchymal stem cells (BMSCs) in experimental models of SCI shows promise as effective therapies. BMSCs secrete various factors that can regulate the microenvironment, which is called paracrine effect. Among these paracrine substances, exosomes are considered to be the most valuable therapeutic factors. Our study found that BMSCs-derived exosomes therapy attenuated cell apoptosis and inflammation response in the injured spinal cord tissues. In in vitro studies, BMSCs-derived exosomes significantly inhibited lipopolysaccharide (LPS)-induced PC12 cell apoptosis, reduced the secretion of pro-inflammatory factors including tumor necrosis factor (TNF)-α and IL (interleukin)-1β and promoted the secretion of anti-inflammatory factors including IL-10 and IL-4. Moreover, we found that LPS-induced protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB (NF-κB) was significantly downregulated after treatment with BMSCs-derived exosomes. In in vivo studies, we found that hindlimb motor function was significantly improved in SCI rats with systemic administration of BMSCs-derived exosomes. We also observed that the expression of pro-apoptotic proteins and pro-inflammatory factors was significantly decreased, while the expression of anti-apoptotic proteins and anti-inflammatory factors were upregulated in SCI rats after exosome treatment. In conclusion, BMSCs-derived exosomes can inhibit apoptosis and inflammation response induced by injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which suggests that BMSCs-derived exosomes are expected to become a new therapeutic strategy for SCI.

Therapeutic Effect of Exosomes Derived From Stem Cells in Spinal Cord Injury: A Systematic Review Based on Animal Studies

“…Six studies reported types of exosomes but did not report specific sources ( 31 , 32 , 38 , 40 , 45 , 46 ). The transplantation route of exosomes included tail vein ( 19 – 21 , 29 – 32 , 34 – 50 , 52 – 56 ), intranasally ( 33 ) and subcutaneous ( 51 ), and one study did not report the route of exosome transplantation ( 28 ); the time transplantation of exosome ranged from 0 ( 19 , 20 , 31 , 38 , 41 , 44 – 47 , 49 ) to 24 h ( 42 , 43 ) after modeling, one study did not report the time of exosome transplantation ( 40 ); dose of exosomes ranged from 20 ( 29 ) to 200 μg ( 28 , 30 – 33 , 36 – 38 , 41 , 43 , 45 – 49 , 53 , 56 ); the control group includes PBS ( 19 – 21 , 28 – 32 , 34 , 35 , 38 , 39 , 41 , 43 – 51 , 53 – 56 ), saline ( 33 , 36 , 37 , 40 , 42 ), and blank ( 52 ). Basic information of the study subjects was summarized in Supplementary Table 2 .…”

“…A total of seven studies reported the expression level of BAX ( 31 , 34 , 35 , 41 , 46 , 47 , 53 ). The meta-analysis results of the random effects model showed that the expression level of BAX of the exosome group was significantly lower than that of the negative control group, and the difference was statistically significant [WDM = −0.70 (−0.98, −0.42), Figure 5 ].…”

Neural stem cell therapy in conjunction with curcumin loaded in niosomal nanoparticles enhanced recovery from traumatic brain injury

“…Previous studies have been revealed that TLR4/NF-κB signaling pathway is activated during the progress of post-TBI secondary injury; therefore, the suppression of the TLR4/NF-κB signaling pathway is a target option for TBI 50 – 52 . The application of curcumin and exosomes derived from stem cells after CNS injuries have been detected as an anti-inflammatory potential by inhibiting TLR4/NF-κB and down-regulating of inflammatory cytokines 14 , 27 , 53 , 54 . These results are in accord with our findings indicating that the expression of TLR4-, NF-κB, and TNF-α-positive cells were significantly decreased in monotherapy-treated rats.…”

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway

“…Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research ( 12 ). BMSCs-derived exosomes could inhibit apoptosis and inflammation response induced by spinal cord injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway ( 25 ). In the present study, FMT led to the activation of the TLR4/MyD88 signaling pathway in the transplanted mice and aggravation of SCI was.…”