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Osteoarthritis is the most common form of arthritis and affects hundreds of millions of people worldwide. While joint damage is a defining feature of the disease, chronic pain is often the symptom that has the greatest impact on daily life. Scientists are searching for new ways to relieve this pain without relying solely on medications that treat symptoms rather than the underlying biological processes.
Researchers from the University of Cambridge, investigated how extracellular vesicles released by mesenchymal stem cells help reduce pain associated with osteoarthritis.
Mesenchymal stem cells have attracted considerable attention because they can promote tissue repair and reduce inflammation. Much of their therapeutic benefit appears to come from the extracellular vesicles they release. These tiny membrane-bound particles carry proteins, lipids, and genetic material that allow cells to communicate with one another.
MSC-EV treatment prevents NGF-induced sensitization of IB4-ve DRG neurons
(a) Representative images of an L4 DRG section showing TrkA expression (magenta) and IB4 binding (cyan), and a merged image; DRG were from a 10-week-old male C57 mouse from which L2-L5 DRG sections were examined. IB4 staining was observed in 43.8±4.8% of neurons and TrkA expression in 36.7±3.5% of all neurons; data displayed as mean ± SEM. (b) IB4 staining is shown in green, recordings were made from IB4-ve neurons. (c) Schematic of experimental design: In vitro studies of DRG neurons performed in cultures with vehicle (control, n = 16 and N = 5; n = neurons and N = mice), 100 ng/ml NGF (n = 20 and N = 5), or NGF + MSC-EVs (106/ml, n = 14 and N = 5), neurons being exposed to NGF for the whole culturing period in the second and third groups, MSC-EVs being added after 24-hours for the NGF + MSC-EVs group. DRG neurons were live-labelled with 2 µg/mL IB4-Alexa488 for 15-20-minutes at 37°C before patch clamp recordings. Only IB4-ve neurons were selected for electrophysiological studies. (d) Comparison of resting membrane potential (RMP) and (e) the minimum current required to induce an action potential (rheobase). Each dot represents an individual DRG neuron, horizontal lines with whiskers show the mean ± SEM. ** = P < 0.01 and **** = P < 0.0001 by one-way ANOVA followed by Tukey’s post hoc test.
Previous research showed that mesenchymal stem cell-derived extracellular vesicles, often called MSC-EVs, reduce pain in mouse models of osteoarthritis by acting directly on sensory neurons, the nerve cells responsible for transmitting pain signals. However, exactly how these extracellular vesicles produced their pain-relieving effects remained unclear.
The researchers discovered that MSC-EVs must first be taken up by sensory neurons before they can work. When proteins on the surface of the extracellular vesicles were removed, the vesicles were no longer efficiently absorbed by the neurons and could not prevent nerve growth factor, or NGF, from making the neurons overly sensitive.
The team also found that the therapeutic effects did not occur immediately. Brief exposure to MSC-EVs was not enough to block NGF-induced sensitization. Instead, the extracellular vesicles triggered changes in gene activity inside the neurons, suggesting that longer-term biological responses are required.
To better understand these changes, the researchers performed small RNA sequencing on the MSC-EVs. This analysis identified three microRNAs, miR-21-5p, miR-148a-3p, and miR-451a, that were likely responsible for the beneficial effects. When the researchers delivered these microRNAs directly into sensory neurons using gold nanoparticles, each reduced NGF-induced sensitization. The combination of all three microRNAs produced the strongest effect.
These findings suggest that extracellular vesicles help control pain by delivering microRNAs that alter gene expression within sensory neurons. Rather than simply blocking pain signals, MSC-EVs appear to reprogram the cells so they become less responsive to pain-producing molecules.
Although the research was performed in mice and additional studies will be needed before these findings can be applied clinically, the work provides valuable insight into how extracellular vesicles function as natural delivery vehicles for therapeutic microRNAs. It also highlights the growing potential of extracellular vesicle-based therapies for treating chronic pain associated with osteoarthritis.
