Human neural stem cell-derived extracellular vesicles protect against Parkinson’s disease pathologies

Abstract

Background Neural stem cells (NSCs) have the ability to generate a variety of functional neural cell types and have a high potential for neuronal cell regeneration and recovery. Thus, they been recognized as the best source of cell therapy for neurodegenerative diseases, such as Parkinson’s disease (PD). Owing to the possibility of paracrine effect-based therapeutic mechanisms and easier clinical accessibility, extracellular vesicles (EVs), which possess very similar bio-functional components from their cellular origin, have emerged as potential alternatives in regenerative medicine. Material and methods EVs were isolated from human fibroblast (HFF) and human NSC (F3 cells). The supernatant of the cells was concentrated by a tangential flow filtration (TFF) system. Then, the final EVs were isolated using a total EV isolation kit. Results In this study, we demonstrate the potential protective effect of human NSC-derived EVs, showing the prevention of PD pathologies in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo mouse models. Human NSC and F3 cell (F3)-derived EVs reduced the intracellular reactive oxygen species (ROS) and associated apoptotic pathways. In addition, F3-derived EVs induced downregulation of pro-inflammatory factors and significantly decreased 6-OHDA-induced dopaminergic neuronal loss in vivo. F3 specific microRNAs (miRNAs) such as hsa-mir-182-5p, hsa-mir-183-5p, hsa-mir-9, and hsa-let-7, which are involved in cell differentiation, neurotrophic function, and immune modulation, were found in F3-derived EVs. Conclusions We report that human NSC-derived EVs show an effective neuroprotective property in an in vitro transwell system and in a PD model. The EVs clearly decreased ROS and pro-inflammatory cytokines. Taken together, these results indicate that NSC-derived EVs could potentially help prevent the neuropathology and progression of PD. Graphical Abstract

Extracellular vesicles in the study of Alzheimer's and Parkinson's diseases: Methodologies applied from cells to biofluids

“…Nevertheless, PP‐based isolation kits as ExoQ (Aulston et al, 2019; Ding et al, 2018; Guo et al, 2020; Park et al, 2020; Wang et al, 2012) and TEI (Lee et al, 2022; Liu et al, 2022; Marzano et al, 2019; Ozansoy et al, 2020; Peng et al, 2022; Tang et al, 2022) are also being employed in some studies, as well as UF kit Exo:pure (Zhdanova et al, 2021). To note, the employment of different methods for EVs isolation from diverse cell lines render in different results.…”

“…Regarding PD, the analysis of EVs from patients' iPSC revealed their potential as a biomarker source for the disease (Candelario et al, 2020). On the other hand, neuronal stem cells-derived EVs appear to exhibit therapeutic potential since it was observed a reduction in ROS levels, caspase 3/7 activity and inflammation mediators in vitro and a decrease in neuronal loss and an anti-inflammatory effect in vivo in a PD mouse model (Lee et al, 2022).…”

Exosomes as CNS Drug Delivery Tools and Their Applications

“…Neural stem cells, in contrast to the aforementioned CNS cells, have the capacity for self-renewal and can differentiate into neurons, astrocytes, oligodendrocytes, etc. Neural stem cell exosomes held great promise in the treatment of neurodegenerative diseases [ 70 ], e.g., human neural stem cell exosomes have a protective effect against Parkinson’s disease [ 71 ] and could ameliorate AD [ 72 ]. Alongside this, extracellular vesicles derived from human neural stem cells have been shown to have good efficacy in the functional recovery of strokes in mice [ 73 ].…”

Combinational treatments of RNA interference and extracellular vesicles in the spinocerebellar ataxia

“…EV-mediated the delivery of DnaJ Homolog Subfamily B Member 6 (DNAJB6) molecular chaperone inhibits the aggregation of polyQ and HTT proteins to delay the onset of HD ( Joshi et al, 2021 ). EVs derive from neural stem cells that target the functional substances to protect damaged neurons by resisting oxidation, apoptosis and inflammation ( Lee et al, 2022 ). Most of the data on the treatment of EVs are concentrated in preclinical trials, but many clinical trials have proved the potential of EVs in diagnosis and monitoring.…”

“…Although the method of encapsulating RNAi in EVs has not been tested in SCA, many studies have proved the feasibility in NDs, autoimmune diseases, tumors, cardiovascular diseases, etc. The EVs-derived from human neural stem cells attenuate the neuroinflammation and ROS-induced apoptosis, and promote the survival of dopaminergic neurons in PD, which may be related to the specific miRNA-embedded in EVs ( Lee et al, 2022 ). Increasing the paracrine miR-146a of cortical astrocytes eliminate their phenotypic abnormalities through pre-miR-146a or dipeptidyl vinyl sulfone and play a neuro-glial repair role in ALS ( Barbosa et al, 2021 ).…”