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Published on: August 16, 2014
Mesenchymal Stem Cell-Extracellular Vesicles Deliver MicroRNAs That Prevent Nerve Growth Factor-Induced Sensory
Lanhui Qiu1, Paula-Milan Rois2, Tuğdem Muslu-Ufuk3
1Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
Abstract:
Osteoarthritis (OA) affects 600 million individuals globally, pain being a hallmark symptom. Emerging clinical evidence supports the use of mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) for pain relief in knee OA. In mice, MSC-EVs ameliorate OA-induced pain and normalize knee-innervating neuron excitability. Moreover, it has been shown that overnight incubation of sensory neurons with MSC-EVs prevents the OA-associated mediator nerve growth factor (NGF) sensitizing sensory neurons. Here, conducting experiments with male and female C57BL/6J mice, we found that protease-mediated MSC-EV "shaving" inhibited MSC-EV internalization into sensory neurons and the ability of MSC-EVs to prevent NGF-induced sensitization. In addition, acute, 10 min, exposure of sensory neurons to MSC-EVs was also insufficient to counteract NGF. We hypothesized that MSC-EVs trigger transcriptional changes and found that inhibiting transcription prevented NGF-induced sensitization. MicroRNAs (miRNAs) can be delivered to cells by MSC-EVs, and certain miRNAs regulate transcription and pain; small RNA sequencing of our MSC-EVs identified three candidate miRNAs, miR-21-5p, miR-148a-3p, and miR-451a. Using gold nanoparticle delivery, each miRNA was able to prevent NGF sensitization of sensory neurons, a combination of all three showing the most pronounced effect. These findings demonstrate that MSC-EVs prevent NGF-induced sensory neuron sensitization via cellular uptake and transcriptional regulation that is mediated by miRNAs.
Insights
Mesenchymal stem cell extracellular vesicles (MSC-EVs) prevent osteoarthritis pain by regulating sensory neuron sensitization. This effect requires MSC-EV internalization and transcriptional changes mediated by specific microRNAs, highlighting a novel therapeutic mechanism.
Area of Science:
- Neuroscience
- Cell Biology
- Biomedical Engineering
Background:
- Osteoarthritis (OA) is a global health issue characterized by pain, affecting 600 million people.
- Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) show promise for managing OA pain.
- MSC-EVs have demonstrated the ability to reduce OA-induced pain and normalize sensory neuron excitability in preclinical models.
Purpose of the Study:
- To elucidate the mechanism by which MSC-EVs prevent nerve growth factor (NGF)-induced sensitization of sensory neurons.
- To investigate the role of MSC-EV internalization and transcriptional regulation in pain modulation.
- To identify specific microRNAs within MSC-EVs responsible for counteracting NGF-induced sensitization.
Main Methods:
- Experiments were conducted using male and female C57BL/6J mice.
- Protease-mediated 'shaving' of MSC-EVs was used to assess the necessity of internalization.
- Inhibition of transcription and gold nanoparticle-mediated delivery of candidate microRNAs (miRNAs) were employed to study miRNA function.
Main Results:
- Protease treatment of MSC-EVs inhibited their internalization into sensory neurons and blocked the prevention of NGF-induced sensitization.
- Short-term (10-minute) exposure to MSC-EVs was insufficient to prevent NGF sensitization.
- Inhibition of transcription prevented NGF-induced sensitization, and specific miRNAs (miR-21-5p, miR-148a-3p, miR-451a) delivered via gold nanoparticles could individually prevent sensitization, with a combination showing the strongest effect.
Conclusions:
- MSC-EVs prevent NGF-induced sensory neuron sensitization through a mechanism involving cellular uptake and transcriptional regulation.
- MicroRNAs encapsulated within MSC-EVs play a critical role in mediating these anti-sensitization effects.
- A specific miRNA cocktail, particularly miR-21-5p, holds potential for therapeutic development in OA pain management.
