miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury

Abstract

Purpose: This review compiles what is known about extracellular vesicles (EVs), their bioactive cargo, and how they might be used to treat radiation-induced brain injury. Radiotherapy (RT) is effective in cancer treatment, but can cause substantial damage to normal central nervous system tissue. Stem cell therapy has been shown to be effective in treating cognitive dysfunction arising from RT, but there remain safety concerns when grafting foreign stem cells into the brain (i.e. immunogenicity, teratoma). These limitations prompted the search for cell-free alternatives, and pointed to EVs that have been shown to have similar ameliorating effects in other tissues and injury models.

Conclusions: EVs are nano-scale and lipid-bound vesicles that readily pass the blood-brain barrier. Arguably the most important bioactive cargo within EVs are RNAs, in particular microRNAs (miRNA). A single miRNA can modulate entire gene networks and signalling within the recipient cell. Determining functionally relevant miRNA could lead to therapeutic treatments where synthetically-derived EVs are used as delivery vectors for miRNA. Stem cell-derived EVs can be effective in treating brain injury including radiation-induced cognitive deficits. Of particular interest are systemic modes of administration which obviate the need for invasive procedures.

Keywords: Extracellular vesicles; cognitive function; miRNA; radiotherapy; stem cells.

Figure 1.

EV treatment in cranially-irradiated athymic nude rats ameliorated radiation-induced neuroinflammation and damage to neuronal structure. (A) Immunohistochemical identification and stereology quantification of activated microglia showed that, compared with controls, irradiation significantly increased the number of activated microglia in all regions of the brain evaluated. Compared with the irradiated (IRR) cohort, IRR+EV animals had significantly lower numbers of activated microglia in the hippocampus, cortex (layer II/III), and amygdala. (B-D) Representative images of Golgi–Cox-impregnated hippocampal tissue sections from Control (Con), IRR, and IRR+EV illustrate the gross disruption of neuronal structure (black) in the dentate gyrus, dentate hilus and CA3 regions of the hippocampus (DG; nuclear fast red counterstained) after cranial irradiation that is resolved in animals receiving EV. Structural parameters of dendritic morphology (length, volume, complexity) quantified in each cohort demonstrate that radiation-induced reductions in dendritic morphology were ameliorated by EV grafting. Data are presented as mean ± SEM (n = 3–4 rats per group). *P ≥ 0.05, **P ≥ 0.01, ***P ≥ 0.001 (ANOVA and Bonferroni’s multiple comparisons test). [Scale bars, 50 μm (B–D).] [adapted from (Baulch et al. 2016)].