Pre-print can be accessed here: https://www.biorxiv.org/content/10.64898/2026.01.12.698945v1
Previously, the research team at the Smith lab, Department of Pharmacology, University of Cambridge, found that mesenchymal stem cell extracellular vesicles (MSC-EV) decrease pain / neuronal sensitisation in mice model osteoarthritis (OA) (see: https://acrjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/art.42177 and https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42353)
Now they have an idea as to how MSC-EVs work!
Cell-cell interactions are key to joint pain: Nerve growth factor (NGF) causes pain (https://www.jneurosci.org/content/13/5/2136.long), is increased in OA (https://onlinelibrary.wiley.com/doi/abs/10.1002/art.1780350315) & sensitises sensory neurons (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42353).
In this new study, researchers confirmed that overnight MSC-EV incubation prevents NGF-induced sensitisation of dorsal root ganglia (DRG) neurons; NGF depolarises resting membrane potential & decreases rheobase, MSC-EVs prevent these effects.
MSC-EVs interact with cells in different ways, including recipient cell internalisation & delivery of complex biomolecular cargo, lipids, miRNA, proteins etc. https://www.nature.com/articles/s41584-023-01010-7
They treated MSC-EVs with trypsin or proteinase K to ‘shave’ extravesicular proteins, which decreased size distribution & shaved MSC-EVs, labelled with PKH26, showed decreased DRG neuron uptake.
Shaved MSC-EVs were less able to prevent NGF-induced sensitisation than untreated MSC-EVs. Suggests that internalisation / biomolecular delivery (or ligand-receptor interaction) are involved.
10-minute MSC-EV incubation did not impact NGF-induced DRG neuron sensitisation, thus rapid post-translational ion channel modification unlikely explains MSC-EV effect.
If MSC-EVs require overnight incubation, might transcription be involved? YES! Inhibiting transcription resulted in MSC-EVs no longer preventing NGF-induced sensitisation.
What MSC-EV cargo might regulate transcription?
miRNAs have been implicated in pain & transcription. Small RNA seq of MSC-EVs revealed abundance of miR-21-5p, miR-148a-3p & miR-451a, all involved in pain/transcription regulation.
DRG neurons are susceptible to lipid-mediated transfection. Researchers thus conjugated oligo + Cy5 or miRNA to glad nanoparticles: efficient DRG neuron uptake & no influence on activity.
Cocktail of miR-21-5p, miR148a-3p & miR451a prevented NGF-induced DRG neuron sensitization, individual potency: miR-21-5p > miR148a-3p > miR451a.
Next steps:
1) working out molecular mechanisms by which miRNAs of interest work
2) examining roles in vivo, e.g. does miR-21-5p ameliorate joint pain in mice?
Project led by Lanhui Qiu with huge thanks to Tim Williams, members of Eric Miska‘s lab, especially Paula Milán-Rois, & all those who supported the work in Department of Pharmacology, University of Cambridge & beyond!
Adapted from: LinkedIn post by Prof Ewan St. John Smith
Posted on 14/01/2026
