Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

Abstract

Background: Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism. Methods: Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms. Results: Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain-and loss-offunction experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p. Conclusion: Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.

MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

“…Meanwhile, the effects were depending on the number of exosomes absorbed by T cells [31]. Also, miRNA had been previously reported to be closely involved in immunosuppression by MSC-EV [14,32]. These experiments demonstrated that MSC-EVs derived miRNA could exert the immunological effects in the therapy.…”

Exosome-Shuttled circSHOC2 from IPASs Regulates Neuronal Autophagy and Ameliorates Ischemic Brain Injury via the miR-7670-3p/SIRT1 Axis

“…For example, exosomes released from WT astrocytes promote neuroprotection and plasticity in spinal cord injury. 28 In the case of ischemia/hypoxia, exosomes derived from endothelial cells can suppress neuronal death, promote neural plasticity, and improve functional recovery. 29 In the current study, we found that exosomes released from IPASs were transmitted to neurons as shuttles carrying circSHOC2, which ameliorated ischemia-induced neuronal apoptosis, indicating that IPAS-EXO-mediated circSHOC2 transport may be sufficient to protect neurons from ischemia-induced damage.…”

Exosomes Derived from Anoxia Preconditioned Mesenchymal Stem Cells alleviate Myocardial Ischemia Reperfusion Injury by Inhibiting Pyroptosis/ Caspase-1 Induced Apoptosis in The Deficiency of Gasdermin D

“…Remote ischemic preconditioning (RIPC) is de ned as repeated stimulation of the nonadjacent tissue, organ with transitory, noninvasive ischemia, which may reduce organ MIRI [28]. Paracrine action was partly thought to underlie the mechanism of RIPC, in which exosomes plays a core role [29], which enlightened us to treat ADSCs with intermittent anoxia. Our ndings revealed that exosomes derived from ADSCs that underwent anoxia preconditioning can serve as promising carriers for suppressing the activation of the cardiac pyroptosis pathway, the latter of which is a core element in inducing myocardial apoptosis.…”