{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:13:59Z","timestamp":1783422839080,"version":"3.54.6"},"reference-count":42,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United Foundation for Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the First Hospital of Dalian Medical University","award":["DMU-1&DICP UN202402"],"award-info":[{"award-number":["DMU-1&DICP UN202402"]}]},{"name":"Liaoning Provincial Key Research and Development Program","award":["2024JH2\/102500038"],"award-info":[{"award-number":["2024JH2\/102500038"]}]},{"name":"Basic Scientific Research Project of Colleges and Universities of the Liaoning Provincial Department of Education","award":["LJ212510161045"],"award-info":[{"award-number":["LJ212510161045"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background:Dysregulated polarization of spinal microglia is a key contributor to the pathophysiology of bone cancer pain (BCP). Bone marrow-derived mesenchymal stromal cells (BMSCs) have demonstrated significant analgesic and microglial-modulatory effects in various pain models. The nuclear factor erythroid 2-related factor 2 (Nrf2)\/heme oxygenase-1 (HO-1) signaling pathway is implicated in the regulation of microglial polarization. However, the specific role and mechanistic basis of intrathecally administered BMSCs in influencing spinal microglial polarization during BCP remain to be fully clarified. In this study, we investigated the impact of intrathecal administration of BMSCs on spinal microglial polarization in a rat model of BCP, and assessed the potential contribution of the Nrf2\/HO-1 signaling pathway to this process.Methods:In a rat model of BCP, animals received three intrathecal injections of 2 \u00d7 106 BMSCs at every other day. Pain behavioral tests, including measurements of the 50% paw withdrawal threshold (PWT) and the number of spontaneous flinches (NSF), were assessed before and after BMSCs administration. The CatWalk automated gait analysis system was employed to quantify BMSC-mediated amelioration of BCP-associated locomotor deficits. Protein expression levels of the pro-inflammatory microglial markers cluster of differentiation 86 (CD86) and inducible nitric oxide synthase (iNOS), along with the anti-inflammatory markers CD206 and Arginase-1 (Arg-1), as well as key components of the Nrf2\/HO-1 signaling pathway, were measured in spinal cord tissues using Western blot and immunofluorescence staining. In addition, a non-contact co-culture system of BMSCs and lipopolysaccharide (LPS)-activated BV2 cells was established. The expression of CD86, iNOS, CD206, Arg-1, and pathway components, together with the mRNA levels of the inflammatory cytokines interleukin (IL)-1\u03b2 and IL-10, were analyzed via Western blot, immunofluorescence, and quantitative real-time PCR (RT-qPCR).Results:Intrathecal injection of BMSCs significantly alleviated established pain behaviors in BCP rats, as evidenced by increased 50% PWT, reduced NSF, and normalized gait parameters. At the molecular level, BMSC treatment downregulated the spinal cord expression of the pro-inflammatory markers CD86 and iNOS while concurrently upregulating the anti-inflammatory markers CD206 and Arg-1. In the co-culture system, BMSC enhanced the activation of the Nrf2\/HO-1 signaling pathway within LPS-stimulated BV2 cells. This enhancement was associated with a reduction in the expression of CD86 and iNOS, an increase in CD206 and Arg-1, decreased levels of IL-1\u03b2, and elevated levels of IL-10.Conclusions:Intrathecal administration of BMSCs effectively attenuates pain in BCP rats by shifting spinal microglial polarization from a pro-inflammatory toward an anti-inflammatory phenotype. The observed modulation of microglial polarization by BMSCs is consistent with an involvement of the Nrf2\/HO-1 signaling pathway.<\/jats:p>","DOI":"10.31083\/jin47234","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:18:12Z","timestamp":1783419492000},"source":"Crossref","is-referenced-by-count":0,"title":["Bone Marrow-Derived Mesenchymal Stromal Cells Alleviate Bone Cancer Pain by Modulating Microglial Polarization: Involvement of the Nrf2\/HO-1 Pathway"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0909-2605","authenticated-orcid":true,"given":"Xinyu","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penghui","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6660-2504","authenticated-orcid":true,"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4310-5077","authenticated-orcid":true,"given":"Ping","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-4770","authenticated-orcid":true,"given":"Qingping","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Snijders RAH, Brom L, Theunissen M, van den Beuken-van Everdingen MHJ. Update on Prevalence of Pain in Patients with Cancer 2022: A Systematic Literature Review and Meta-Analysis. Cancers. 2023; 15: 591.","DOI":"10.3390\/cancers15030591"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Aielli F, Ponzetti M, Rucci N. Bone Metastasis Pain, from the Bench to the Bedside. International Journal of Molecular Sciences. 2019; 20: 280.","DOI":"10.3390\/ijms20020280"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Paice JA, Bohlke K, Barton D, Craig DS, El-Jawahri A, Hershman DL, et al. Use of Opioids for Adults With Pain From Cancer or Cancer Treatment: ASCO Guideline. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023; 41: 914\u2013930.","DOI":"10.1200\/JCO.22.02198"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochemical Pharmacology. 2020; 180: 114147.","DOI":"10.1016\/j.bcp.2020.114147"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet (London, England). 2019; 393: 1558\u20131568.","DOI":"10.1016\/S0140-6736(19)30430-1"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Zheng XQ, Wu YH, Huang JF, Wu AM. Neurophysiological mechanisms of cancer-induced bone pain. Journal of Advanced Research. 2021; 35: 117\u2013127.","DOI":"10.1016\/j.jare.2021.06.006"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Falk S, Dickenson AH. Pain and nociception: mechanisms of cancer-induced bone pain. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2014; 32: 1647\u20131654.","DOI":"10.1200\/JCO.2013.51.7219"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nature Medicine. 2017; 23: 1018\u20131027.","DOI":"10.1038\/nm.4397"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Zhang WJ, Liu JP, Xu YS, Zuo C, Liao JX, Zhu FQ, et al. Olfactory ensheathing cell transplantation alleviates cancer pain by inhibiting P2X7 receptor expression-mediated activation of microglia. International Journal of Surgery (London, England). 2025; 111: 7727\u20137745.","DOI":"10.1097\/JS9.0000000000002976"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Huang LQ, Yan TX, Wang BS, Li H, Zhou NB. ZC3H15 suppression ameliorates bone cancer pain through inhibiting neuronal oxidative stress and microglial inflammation. 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Antinociceptive effect of intrathecal injection of miR-9-5p modified mouse bone marrow mesenchymal stem cells on a mouse model of bone cancer pain. Journal of Neuroinflammation. 2020; 17: 85.","DOI":"10.1186\/s12974-020-01765-w"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Kan H, Huang J, Gui X, Tian W, Fan L, Chen X, et al. Bone marrow mesenchymal stem cells improve bone cancer pain by inhibiting p38MAPK phosphorylation and microglia activation. The Korean Journal of Pain. 2025; 38: 116\u2013127.","DOI":"10.3344\/kjp.24374"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Shen W, Hu XM, Liu YN, Han Y, Chen LP, Wang CC, et al. CXCL12 in astrocytes contributes to bone cancer pain through CXCR4-mediated neuronal sensitization and glial activation in rat spinal cord. Journal of Neuroinflammation. 2014; 11: 75.","DOI":"10.1186\/1742-2094-11-75"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. Journal of Neuroscience Methods. 1994; 53: 55\u201363.","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Ding Z, Liang X, Wang J, Song Z, Guo Q, Sch\u00e4fer MKE, et al. Inhibition of spinal ferroptosis-like cell death alleviates hyperalgesia and spontaneous pain in a mouse model of bone cancer pain. Redox Biology. 2023; 62: 102700.","DOI":"10.1016\/j.redox.2023.102700"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Hu XM, Yang W, Du LX, Cui WQ, Mi WL, Mao-Ying QL, et al. Vascular Endothelial Growth Factor A Signaling Promotes Spinal Central Sensitization and Pain-related Behaviors in Female Rats with Bone Cancer. Anesthesiology. 2019; 131: 1125\u20131147.","DOI":"10.1097\/ALN.0000000000002916"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Song ZP, Xiong BR, Guan XH, Cao F, Manyande A, Zhou YQ, et al. Minocycline attenuates bone cancer pain in rats by inhibiting NF-\u03baB in spinal astrocytes. Acta Pharmacologica Sinica. 2016; 37: 753\u2013762.","DOI":"10.1038\/aps.2016.1"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Xu C, Wang Y, Ni C, Xu M, Yin C, He Q, et al. Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models. EMBO Reports. 2024; 25: 5429\u20135455.","DOI":"10.1038\/s44319-024-00292-6"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-\u03b2 secretion. The Journal of Clinical Investigation. 2015; 125: 3226\u20133240.","DOI":"10.1172\/JCI80883"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Fuseya S, Yamamoto K, Minemura H, Yamaori S, Kawamata T, Kawamata M. Systemic QX-314 Reduces Bone Cancer Pain through Selective Inhibition of Transient Receptor Potential Vanilloid Subfamily 1-expressing Primary Afferents in Mice. Anesthesiology. 2016; 125: 204\u2013218.","DOI":"10.1097\/ALN.0000000000001152"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Wu W, Zhang X, Wang S, Li T, Hao Q, Li S, et al. Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain. Neuropharmacology. 2022; 217: 109206.","DOI":"10.1016\/j.neuropharm.2022.109206"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Jin GL, Hong LM, Liu HP, Yue RC, Shen ZC, Yang J, et al. Koumine modulates spinal microglial M1 polarization and the inflammatory response through the Notch-RBP-J\u03ba signaling pathway, ameliorating diabetic neuropathic pain in rats. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology. 2021; 90: 153640.","DOI":"10.1016\/j.phymed.2021.153640"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Wu P, Zhou G, Wu X, Lv R, Yao J, Wen Q. P2X7 receptor induces microglia polarization to the M1 phenotype in cancer-induced bone pain rat models. Molecular Pain. 2022; 18: 17448069211060962.","DOI":"10.1177\/17448069211060962"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Ochocka N, Kaminska B. Microglia Diversity in Healthy and Diseased Brain: Insights from Single-Cell Omics. International Journal of Molecular Sciences. 2021; 22: 3027.","DOI":"10.3390\/ijms22063027"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Gui X, Wang H, Wu L, Tian S, Wang X, Zheng H, et al. Botulinum toxin type A promotes microglial M2 polarization and suppresses chronic constriction injury-induced neuropathic pain through the P2X7 receptor. Cell & Bioscience. 2020; 10: 45.","DOI":"10.1186\/s13578-020-00405-3"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Zhao Y, Li T, Zhang L, Yang J, Zhao F, Wang Y, et al. TRAF6 promotes spinal microglial M1 polarization to aggravate neuropathic pain by activating the c-JUN\/NF-kB signaling pathway. Cell Biology and Toxicology. 2024; 40: 54.","DOI":"10.1007\/s10565-024-09900-6"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Nakagawa Y, Chiba K. Diversity and plasticity of microglial cells in psychiatric and neurological disorders. Pharmacology & Therapeutics. 2015; 154: 21\u201335.","DOI":"10.1016\/j.pharmthera.2015.06.010"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nature Neuroscience. 2016; 19: 987\u2013991.","DOI":"10.1038\/nn.4338"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Cherry JD, Olschowka JA, O'Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. Journal of Neuroinflammation. 2014; 11: 98.","DOI":"10.1186\/1742-2094-11-98"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Pol O. The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids. Medicinal Research Reviews. 2021; 41: 136\u2013155.","DOI":"10.1002\/med.21726"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Tonelli C, Chio IIC, Tuveson DA. Transcriptional Regulation by Nrf2. Antioxidants & Redox Signaling. 2018; 29: 1727\u20131745.","DOI":"10.1089\/ars.2017.7342"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Sun S, Fan Z, Liu X, Wang L, Ge Z. Microglia TREM1-mediated neuroinflammation contributes to central sensitization via the NF-\u03baB pathway in a chronic migraine model. 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