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Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis.

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cam.depositDate2022-08-30
cam.issuedOnline2022-09-19
cam.orpheus.counter3
cam.orpheus.successMon Sep 26 08:22:36 BST 2022 - Embargo updated
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.81339
dc.contributor.authorAi, Minji
dc.contributor.authorHotham, William E
dc.contributor.authorPattison, Luke A
dc.contributor.authorMa, Qingxi
dc.contributor.authorHenson, Frances MD
dc.contributor.authorSmith, Ewan St John
dc.contributor.orcidSmith, Ewan St John [0000-0002-2699-1979]
dc.date.accessioned2022-08-30T23:30:31Z
dc.date.available2022-08-30T23:30:31Z
dc.date.issued2022-09-19
dc.date.updated2022-08-30T07:08:55Z
dc.description.abstractOBJECTIVE: Mesenchymal stem/stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) have been reported to alleviate pain in patients with knee osteoarthritis (OA). We undertook this study to determine whether MSCs and/or MSC-EVs reduce OA pain through influencing sensory neuron excitability in OA joints. METHODS: We induced knee OA in adult male C57BL/6J mice through destabilization of the medial meniscus (DMM) surgery. Mice were sorted into 4 experimental groups with 9 mice per group as follows: unoperated sham, untreated DMM, DMM plus MSC treatment, and DMM plus MSC-EV treatment. Treated mice received either MSCs at week 14 postsurgery or MSC-EVs at weeks 12 and 14 postsurgery. Mouse behavior was evaluated by digging and rotarod tests and the Digital Ventilated Cage system. At week 16, mouse knee joints were harvested for histology, and dorsal root ganglion (DRG) neurons were isolated for electrophysiology. Furthermore, we induced hyperexcitability in DRG neurons in vitro using nerve growth factor (NGF) then treated these neurons with or without MSC-EVs and evaluated neuron excitability. RESULTS: MSC- and MSC-EV-treated DMM-operated mice did not display pain-related behavior changes (in locomotion, digging, and sleep) that occurred in untreated DMM-operated mice. The absence of pain-related behaviors in MSC- and MSC-EV-treated mice was not the result of reduced joint damage but rather a lack of knee-innervating sensory neuron hyperexcitability that was observed in untreated DMM-operated mice. Furthermore, we found that NGF-induced sensory neuron hyperexcitability is prevented by MSC-EV treatment (P < 0.05 versus untreated NGF-sensitized neurons when comparing action potential threshold). CONCLUSION: MSCs and MSC-EVs may reduce pain in OA by direct action on peripheral sensory neurons.
dc.description.sponsorshipThis work was supported by funding from Versus Arthritis (RG21973) to E.St.J.S and Horizon 2020 (RG90905) and Innovate UK (RG87266) to F.M.D.H.
dc.identifier.doi10.17863/CAM.87953
dc.identifier.eissn2326-5205
dc.identifier.issn2326-5191
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/340515
dc.language.isoeng
dc.publisherWiley
dc.publisher.departmentDepartment of Pharmacology
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleRole of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis.
dc.typeArticle
dcterms.dateAccepted2022-09-08
prism.publicationNameArthritis Rheumatol
pubs.funder-project-idArthritis Research UK (11600/21973)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1002/art.42353

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