{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:38Z","timestamp":1787022098771,"version":"build-2736575974"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T00:00:00Z","timestamp":1644796800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomimetics Sympathies Inc.","award":["C2017-128"],"award-info":[{"award-number":["C2017-128"]}]},{"name":"Biomimetics Sympathies Inc.","award":["C2019-197"],"award-info":[{"award-number":["C2019-197"]}]},{"name":"Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science","award":["20K07750"],"award-info":[{"award-number":["20K07750"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs), which are isolated from adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), or bone marrow, have therapeutic potential including anti-inflammatory and immunomodulatory activities. It was recently reported that MSCs are also effective as a therapeutic treatment for neuropathic pain, although the underlying mechanisms have yet to be resolved. Therefore, in this study, we investigated the effects of human AD- and UC-MSCs on neuropathic pain and its mechanisms using rat models of partial sciatic nerve ligation (PSNL). AD- or UC-MSCs were intravenously administered 4 days after PSNL. Antinociceptive effects were then evaluated using the von Frey and weight-bearing tests. We found that, 3\u20139 days after the administration of AD- or UC-MSCs to PSNL-exposed rats, both the mechanical threshold and differences in weight-bearing of the right and left hind paws were significantly improved. To reveal the potential underlying antinociceptive mechanisms of MSCs, the levels of activation transcription factor 3- and ionized calcium-binding adapter molecule 1-positive cells were measured by immunohistochemical analysis. AD- and UC-MSCs significantly decreased the levels of these proteins that were induced by PSNL in the dorsal root ganglia. Additionally, UC-MSC significantly improved the PSNL-induced decrease in the myelin basic protein level in the sciatic nerve, indicating that UC-MSC reversed demyelination of the sciatic nerve produced by PSNL. These data suggest that AD- and UC-MSCs may help in the recovery of neuropathic pain via the different regulation; AD-MSCs exhibited their effects via suppressed neuronal damage and anti-inflammatory actions, while UC-MSCs exhibited their effects via suppressed neuronal damage, anti-inflammatory actions and remyelination.<\/jats:p>","DOI":"10.1371\/journal.pone.0262892","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T13:27:02Z","timestamp":1644845222000},"page":"e0262892","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":34,"title":["Intravenous administration of human mesenchymal stem cells derived from adipose tissue and umbilical cord improves neuropathic pain via suppression of neuronal damage and anti-inflammatory actions in rats"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1673-6074","authenticated-orcid":true,"given":"Kanako","family":"Miyano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minori","family":"Ikehata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Ohshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Nose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei-ichi","family":"Yoshihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Oki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Shiraishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaki","family":"Uzu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Nonaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Higami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhito","family":"Uezono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,14]]},"reference":[{"issue":"7","key":"pone.0262892.ref001","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1096\/fj.201601183R","article-title":"Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop","volume":"31","author":"H Shindou","year":"2017","journal-title":"FASEB J"},{"issue":"6","key":"pone.0262892.ref002","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/aps.2013.50","article-title":"Mesenchymal stem cells: a new trend for cell therapy","volume":"34","author":"X Wei","year":"2013","journal-title":"Acta Pharmacol Sin"},{"key":"pone.0262892.ref003","doi-asserted-by":"crossref","first-page":"2638305","DOI":"10.1155\/2017\/2638305","article-title":"The holy grail of orthopedic surgery: Mesenchymal stem cells-their current uses and potential applications","volume":"2017","author":"R Berebichez-Fridman","year":"2017","journal-title":"Stem Cells Int"},{"issue":"4","key":"pone.0262892.ref004","first-page":"315","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells","volume":"8","author":"M Dominici","year":"2006","journal-title":"The International Society for Cellular Therapy position statement. Cytotherapy"},{"key":"pone.0262892.ref005","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/sctm.16-0484","article-title":"Concise review: Mesenchymal stem cells in cardiovascular regeneration: Emerging research directions and clinical applications","volume":"6","author":"M Majka","year":"2017","journal-title":"Stem Cells Transl Med"},{"issue":"4","key":"pone.0262892.ref006","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2174\/1574888X15666200214112908","article-title":"A review on stem cell therapy for neuropathic pain","volume":"15","author":"S Asgharzade","year":"2020","journal-title":"Curr Stem Cell Res Ther"},{"key":"pone.0262892.ref007","first-page":"8179013","article-title":"Conditioned medium of bone marrow-derived mesenchymal stromal cells as a therapeutic approach to neuropathic pain: A preclinical evaluation","volume":"2018","author":"KB Gama","year":"2018","journal-title":"Stem Cells Int"},{"issue":"1","key":"pone.0262892.ref008","doi-asserted-by":"crossref","first-page":"9904","DOI":"10.1038\/s41598-017-09487-5","article-title":"Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain","volume":"7","author":"AT Brini","year":"2017","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0262892.ref009","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1007\/s11064-016-2051-5","article-title":"Intrathecal injection of human umbilical cord-derived mesenchymal stem cells ameliorates neuropathic pain in rats","volume":"41","author":"C Chen","year":"2016","journal-title":"Neurochem Res"},{"issue":"9","key":"pone.0262892.ref010","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1007\/s00221-017-5000-x","article-title":"Inhibition of neuropathic hyperalgesia by intrathecal bone marrow stromal cells is associated with alteration of multiple soluble factors in cerebrospinal fluid","volume":"235","author":"G Fischer","year":"2017","journal-title":"Exp Brain Res"},{"key":"pone.0262892.ref011","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3389\/fnint.2011.00079","article-title":"Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice","volume":"5","author":"D Siniscalco","year":"2011","journal-title":"Front Integr Neurosci"},{"issue":"2","key":"pone.0262892.ref012","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0304-3959(90)91074-S","article-title":"A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury","volume":"43","author":"Z Seltzer","year":"1990","journal-title":"Pain"},{"issue":"2","key":"pone.0262892.ref013","doi-asserted-by":"crossref","first-page":"e0148185","DOI":"10.1371\/journal.pone.0148185","article-title":"Adipose-derived mesenchymal stem cells restore impaired mucosal immune responses in aged mice","volume":"11","author":"K Aso","year":"2016","journal-title":"PLOS ONE"},{"issue":"13","key":"pone.0262892.ref014","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.3390\/ijms20133271","article-title":"Carboplatin enhances the activity of human transient receptor potential ankyrin 1 through the cyclic AMP-protein kinase A-A-kinase anchoring protein (AKAP) pathways","volume":"20","author":"K Miyano","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0262892.ref015","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"SR Chaplan","year":"1994","journal-title":"J Neurosci Methods"},{"key":"pone.0262892.ref016","doi-asserted-by":"crossref","first-page":"14648","DOI":"10.1038\/srep14648","article-title":"Dynamic weight bearing is an efficient and predictable method for evaluation of arthritic nociception and its pathophysiological mechanisms in mice","volume":"5","author":"AU Quadros","year":"2015","journal-title":"Sci Rep"},{"key":"pone.0262892.ref017","doi-asserted-by":"crossref","first-page":"723","DOI":"10.3389\/fphar.2017.00723","article-title":"Long-Chain Omega-3 Fatty Acids Supplementation Accelerates Nerve Regeneration and Prevents Neuropathic Pain Behavior in Mice","volume":"8","author":"RV Silva","year":"2017","journal-title":"Front Pharmacol"},{"issue":"13","key":"pone.0262892.ref018","doi-asserted-by":"crossref","first-page":"7947","DOI":"10.1073\/pnas.1331358100","article-title":"Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2","volume":"100","author":"C Abbadie","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1\u20132","key":"pone.0262892.ref019","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jneuroim.2010.08.013","article-title":"The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines","volume":"229","author":"PJ Austin","year":"2010","journal-title":"J Neuroimmunol"},{"issue":"1","key":"pone.0262892.ref020","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0306-4522(02)00065-9","article-title":"Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat","volume":"112","author":"P Hu","year":"2002","journal-title":"Neuroscience"},{"issue":"1","key":"pone.0262892.ref021","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1006\/exnr.1996.0142","article-title":"Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice","volume":"141","author":"RR Myers","year":"1996","journal-title":"Exp Neurol"},{"issue":"11","key":"pone.0262892.ref022","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/nn1992","article-title":"The neuropathic pain triad: neurons, immune cells and glia","volume":"10","author":"J Scholz","year":"2007","journal-title":"Nat Neurosci"},{"key":"pone.0262892.ref023","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.expneurol.2016.11.006","article-title":"Therapeutic potential of mesenchymal stem cells for the treatment of diabetic peripheral neuropathy","volume":"288","author":"M Monfrini","year":"2017","journal-title":"Exp Neurol"},{"issue":"S 1","key":"pone.0262892.ref024","doi-asserted-by":"crossref","first-page":"175","DOI":"10.7205\/MILMED-D-16-00096","article-title":"Comparative efficacy of multiple variables of mesenchymal stem cell transplantation for the treatment of neuropathic pain in rats","volume":"182","author":"L Liu","year":"2017","journal-title":"Mil Med"},{"issue":"1","key":"pone.0262892.ref025","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/j.pain.0000000000001395","article-title":"Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury-induced pain in rats","volume":"160","author":"SJ Shiue","year":"2019","journal-title":"Pain"},{"issue":"1","key":"pone.0262892.ref026","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3390\/toxins8010027","article-title":"Preventive effects of bee venom derived phospholipase A2 on oxaliplatin-induced neuropathic pain in mice","volume":"8","author":"D Li","year":"2016","journal-title":"Toxins (Basel)"},{"issue":"2","key":"pone.0262892.ref027","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/01.LAB.0000056993.28149.BF","article-title":"Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages","volume":"83","author":"M Mueller","year":"2003","journal-title":"Lab Invest"},{"issue":"2","key":"pone.0262892.ref028","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0165-5728(01)00324-1","article-title":"Expression of interleukin-1 beta in rat dorsal root ganglia","volume":"118","author":"JC Copray","year":"2001","journal-title":"J Neuroimmunol"},{"issue":"4","key":"pone.0262892.ref029","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1097\/ALN.0000000000001010","article-title":"Resolvin D1 inhibits mechanical hypersensitivity in sciatica by modulating the expression of nuclear factor-\u03baB, phospho-extracellular signal-regulated kinase, and pro- and antiinflammatory cytokines in the spinal cord and dorsal root ganglion","volume":"124","author":"ZH Liu","year":"2016","journal-title":"Anesthesiology"},{"key":"pone.0262892.ref030","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/978-3-540-79090-7_12","article-title":"Cytokine and chemokine regulation of sensory neuron function","volume":"194","author":"RJ Miller","year":"2009","journal-title":"Handb Exp Pharmacol"},{"issue":"35","key":"pone.0262892.ref031","doi-asserted-by":"crossref","first-page":"12533","DOI":"10.1523\/JNEUROSCI.2840-11.2011","article-title":"Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1\u03b2 and TNF: implications for neuropathic pain","volume":"31","author":"S Nadeau","year":"2011","journal-title":"J Neurosci"},{"key":"pone.0262892.ref032","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/0028-3908(94)90171-6","article-title":"Interleukin-1 beta induced-desArg9bradykinin-mediated thermal hyperalgesia in the rat","volume":"33","author":"MN Perkins","year":"1994","journal-title":"Neuropharmacology"},{"issue":"4","key":"pone.0262892.ref033","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1159\/000494652","article-title":"Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NF\u03baB p65 subunit in spinal cord injury","volume":"50","author":"L Wang","year":"2018","journal-title":"Cell Physiol Biochem"},{"key":"pone.0262892.ref034","doi-asserted-by":"crossref","first-page":"153166","DOI":"10.1016\/j.phymed.2019.153166","article-title":"Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-\u03b1\/IL-1\u03b2-mediated NF-\u03baB activation and Schwann cell demyelination","volume":"67","author":"LW Chu","year":"2020","journal-title":"Phytomedicine"},{"issue":"11","key":"pone.0262892.ref035","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.3390\/ijms17111867","article-title":"Tonsil-derived mesenchymal stem cells differentiate into a Schwann cell phenotype and promote peripheral nerve regeneration","volume":"17","author":"N Jung","year":"2016","journal-title":"Int J Mol Sci"},{"key":"pone.0262892.ref036","doi-asserted-by":"crossref","first-page":"44","DOI":"10.21037\/sci.2019.10.06","article-title":"Safety and efficacy of stem cell therapy for treatment of neural damage in patients with multiple sclerosis","volume":"6","author":"M Jafarzadeh Bejargafshe","year":"2019","journal-title":"Stem Cell Investig"},{"key":"pone.0262892.ref037","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/1745-6215-12-62","article-title":"The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments","volume":"12","author":"P Connick","year":"2011","journal-title":"Trials"},{"issue":"1","key":"pone.0262892.ref038","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12967-018-1433-7","article-title":"Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis","volume":"16","author":"NH Riordan","year":"2018","journal-title":"J Transl Med"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262892","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T13:27:30Z","timestamp":1644845250000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262892"}},"subtitle":[],"editor":[{"given":"Masabumi","family":"Minami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,14]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262892","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,14]]}}}