Efficacy of miRNA-modified mesenchymal stem cell extracellular vesicles in spinal cord injury: A systematic review of the literature and network meta-analysis

Abstract

BackgroundAlthough some previous studies have indicated that extracellular vesicles (EVs) secreted from miRNA-modified mesenchymal stem cells (MSCs) may be more effective as compared with control EVs in the treatment of rats with spinal cord injuries (SCI), the efficacy of this treatment modality remains controversial.ObjectivesThe current study comprehensively evaluated the efficacy of different administered doses of EVs, including miRNA-overexpressing MSCs-derived EVs, among SCI rats. The efficacy of EVs' treatment was evaluated in different SCI models to provide evidence for preclinical trials.MethodsWe extensively searched the following databases to identify relevant studies: PubMed, Embase, Scopus, The Cochrane Library, and Web of Science (from inception to July 20, 2022). Two trained investigators independently screened literature, extracted the data, and evaluated literature quality.ResultsThirteen studies were included in this network meta-analysis. The results demonstrated that miRNA-overexpressing MSCs-derived EVs (100 and 200 μg of total protein of EVs) significantly improved hind limb motor function in rats at early stages of SCI (i.e., at 3 days after injury) as compared with EVs (100 and 200 μg of total protein of EVs, respectively). However, in the middle and late stages (14 and 28 days), there were no statistically significant differences between EVs with 200 μg dosages and miRNA-loaded EVs with 100 μg dosages. In the late stages (28 days), there were no statistically significant differences between EVs with 100 μg dosages and miRNA-loaded EVs with 200 μg dosages. We found that miRNA-overexpressing MSCs-derived EVs significantly improved motor function among early-stage SCI rats in a compression and contusion model (3 days) as compared with MSCs-derived EVs and miRNA-overexpressing MSCs-derived EVs likewise significantly improved motor function among SCI rats in a contusion model at middle and late stages (14 and 28 days).ConclusionOur results suggest that miRNA-overexpressing MSCs-derived EVs (200 μg of total protein of EVs) may be the best choice for the effective treatment of SCI, and miRNA-overexpressing MSCs-derived EVs may likewise be the best choice for treating contusions. However, there are some risks of bias in our included studies, and the mechanisms underlying the efficacy of EVs remain unclear.Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=282051, identifier: CRD42021282051.

Epigenetic processes associated with neonatal spinal transection

“…Indeed, one proposed treatment effort is the delivery of engineered extracellular vesicles (EV's) containing a cocktail of miRNA's and enzymes to alter DNA methylation, histone modifications, and posttranscriptional modification (Gupta et al., 2023) after SCI. One recent meta‐analysis assessing the efficacy of miRNA associated EV delivery to promote recovery was efficacious in improving hindlimb motor function if delivered within 2 weeks of injury (Yang et al., 2022), which aligns with our observed heightened BDNF expression levels and improved functional recovery after 2 weeks observed here.…”

Mesenchymal stem cells (MSCs) and MSC‐derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome

“…Furthermore, administration of MSC‐exosomes overexpressing miR‐126 markedly suppressed microglial activation as well as the production of inflammatory mediators in a rat model of stroke 150 . Confirming these results, other studies have demonstrated the significant protective effects of exosomes derived from miR‐modified MSCs by suppressing inflammatory pathways in the CNS 151–153 …”

“…150 Confirming these results, other studies have demonstrated the significant protective effects of exosomes derived from miR-modified MSCs by suppressing inflammatory pathways in the CNS. [151][152][153] In sum, the transplantation of MSCs and their exosomes can provide an effective and safe nonpharmaceutical treatment for CNS diseases via the regulation of neuroinflammation.…”

Mesenchymal stem cell‐derived extracellular vesicles: Recent therapeutics and targeted drug delivery advances

“…Some extensively used modification techniques include click chemistry‐based strategies for EV surface labelling using fluorescent beads, quantum dots, and supermagnetic particles, as shown in Figure 2. Studies indicate that MSC‐EVs have shown substantial therapeutic potential in various disease conditions without any modification (Chen et al., 2023, Rani et al., 2015, Yang et al., 2023, Zeng et al., 2022). However, these EVs are often complemented with specific formulations, adhesives, or hydrogels to increase their intrinsic therapeutic efficiencies (Liu et al., 2023, Wang et al., 2023).…”