miR-100a-5p-enriched exosomes derived from mesenchymal stem cells enhance the anti-oxidant effect in a Parkinson’s disease model via regulation of Nox4/ROS/Nrf2 signaling

Abstract

Background The pathogenesis of Parkinson's disease (PD) has not been fully elucidated, and there are no effective disease-modifying drugs for the treatment of PD. Mesenchymal stem cells have been used to treat several diseases, but are not readily available. Methods Here, we used phenotypically uniform trophoblast stage-derived mesenchymal stem cells (T-MSCs) from embryonic stem cells, which are capable of stable production, and their exosomes (T-MSCs-Exo) to explore the molecular mechanisms involved in dopaminergic (DA) neuron protection in PD models using experimental assays (e.g., western blotting, immunofluorescence and immunohistochemistry staining). Results We assessed the levels of DA neuron injury and oxidative stress in MPTP-induced PD mice and MPP+-induced MN9D cells after treating them with T-MSCs or T-MSCs-Exo. Furthermore, T-MSCs-Exo miRNA sequencing analysis revealed that miR-100-5p-enriched T-MSCs-Exo directly targeted the 3′ UTR of NOX4, which could protect against the loss of DA neurons, maintain nigro-striatal system function, ameliorate motor deficits, and reduce oxidative stress via the Nox4-ROS-Nrf2 axis in PD models. Conclusions The study suggests that miR-100-5p-enriched T-MSCs-Exo may be a promising biological agent for the treatment of PD. Graphical Abstract Schematic summary of the mechanism underlying the neuroprotective actions of T-MSCs-Exo in PD. T-MSCs Exo may inhibit the expression level of the target gene NOX4 by delivering miR-100-5p, thereby reducing ROS production and alleviating oxidative stress via the Nox4-ROS-Nrf2 axis, thus improving DA neuron damage in PD.

Nrf2 activation: a key mechanism in stem cell exosomes-mediated therapies

“…These exosomes contribute to the maintenance of nigrostriatal system function, improvement of motor impairments, and reduction of oxidative stress by the regulation of the NADPH oxidase 4 (Nox4)-ROS-Nrf2 axis (Fig. 1 ) [ 199 ].…”

Stem cell-derived extracellular vesicles in the therapeutic intervention of Alzheimer's Disease, Parkinson's Disease, and stroke

“…The T-MSC-EVs were found to directly target the 3' untranslated region of the NOX4 gene. This specific targeting mechanism was shown to provide neuroprotection against the degeneration of dopamine neurons, maintain the integrity and functionality of the nigrostriatal pathway, reduce motor impairments, and decrease oxidative stress via the Nox4-ROS-Nrf2 signaling pathway in PD models 63 . Accumulating evidences have shown that treatment with MSC-derived EVs markedly ameliorated in vivo ischemia/reperfusion brain injury, enhanced neuron viability in vitro, and reduced apoptosis.…”