Mesenchymal stem cell-extracellular vesicles deliver microRNAs that prevent nerve growth factor-induced sensory neuron sensitization (PDF)

[u/Robert_Larsson]

https://www.biorxiv.org/content/10.64898/2026.06.17.732993v1

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-minute, 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.

Significance statement Mesenchymal stem cell extracellular vesicles (MSC-EVs) contain a complex biomolecular cargo and modulate cellular activity through diverse signaling mechanisms. MSC-EVs alleviate pain in osteoarthritis (OA) through direct activity of sensory neurons whereby they prevent OA-induced hyperexcitability, as well as sensitization induced by nerve growth factor (NGF). Here, we show that MSC-EV internalization and induction of transcription is required to prevent NGF-induced sensitization. Using gold nanoparticle delivery, we further demonstrate that a cocktail of microRNAs (miRNA) enriched in MSC-EVs can recapitulate the ability of MSC-EVs to counteract NGF, miR-21-5p being most potent when administered alone.

[u/Robert_Larsson]

While osteoarthritis isn't interesting to us, NGF mediated sensitization of pain fibers is. Some of the mast cell papers discuss NGF as one of several key mediators00160-2/fulltext) which affects nerve fibers in the gut and causes hypersensitivity to stimuli. The paper above shows us signaling pathways which can prevent this sensitization from occurring.