{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:50:19Z","timestamp":1788177019069,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T00:00:00Z","timestamp":1699315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health and Welfare","award":["HH21C0027"],"award-info":[{"award-number":["HH21C0027"]}]},{"name":"Ministry of Health and Welfare","award":["HR16C0002"],"award-info":[{"award-number":["HR16C0002"]}]},{"name":"Ministry of Health and Welfare","award":["2021M3E5E5095899"],"award-info":[{"award-number":["2021M3E5E5095899"]}]},{"name":"Korean Fund for Regenerative Medicine","award":["HH21C0027"],"award-info":[{"award-number":["HH21C0027"]}]},{"name":"Korean Fund for Regenerative Medicine","award":["HR16C0002"],"award-info":[{"award-number":["HR16C0002"]}]},{"name":"Korean Fund for Regenerative Medicine","award":["2021M3E5E5095899"],"award-info":[{"award-number":["2021M3E5E5095899"]}]},{"DOI":"10.13039\/501100014188","name":"the Ministry of Science and ICT","doi-asserted-by":"publisher","award":["HH21C0027"],"award-info":[{"award-number":["HH21C0027"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"the Ministry of Science and ICT","doi-asserted-by":"publisher","award":["HR16C0002"],"award-info":[{"award-number":["HR16C0002"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"the Ministry of Science and ICT","doi-asserted-by":"publisher","award":["2021M3E5E5095899"],"award-info":[{"award-number":["2021M3E5E5095899"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The therapeutic potential of Mesenchymal stem cells (MSCs) for the treatment of Intervertebral disc (IVD) degeneration can be enhanced by amplifying specific cytokines and proteins. This study aimed to investigate the therapeutic potential of tetracycline-off system-engineered tonsil-derived mesenchymal stem cells (ToMSC-Tetoff-TGF\u03b21-IGF1-BMP7) for treating intervertebral disc (IVD) degeneration. ToMSCs were isolated from a tonsillectomy patient and genetically modified with four distinct plasmids via CRISPR\/Cas9-mediated knock-in gene editing. Transgene expression was confirmed through immunofluorescence, western blots, and an enzyme-linked immunosorbent assay for transforming growth factor beta 1 (TGF\u03b21) protein secretion, and the effect of MSC-TetOff-TGF\u03b21-IGF1-BMP7 on disc injury was assessed in a rat model. The ToMSC-Tetoff-TGF\u03b21-IGF1-BMP7 treatment exhibited superior therapeutic effects compared to ToMSC-TGF\u03b21, and ToMSC-SDF1\u03b1 implantation groups, stimulating the regeneration of nucleus pulposus (NP) cells crucial for IVD. The treatment showed potential to restore the structural integrity of the extracellular matrix (ECM) by upregulating key molecules such as aggrecan and type II collagen. It also exhibited anti-inflammatory properties and reduced pain-inducing neuropeptides. ToMSC-Tetoff-TGF\u03b21-IGF1-BMP7 holds promise as a novel treatment for IVD degeneration. It appears to promote NP cell regeneration, restore ECM structure, suppress inflammation, and reduce pain. However, more research and clinical trials are required to confirm its therapeutic potential.<\/jats:p>","DOI":"10.3390\/ijms242216024","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T10:52:47Z","timestamp":1699354367000},"page":"16024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Enhanced Intervertebral Disc Repair via Genetically Engineered Mesenchymal Stem Cells with Tetracycline Regulatory System"],"prefix":"10.3390","volume":"24","author":[{"given":"Yeji","family":"Kim","sequence":"first","affiliation":[{"name":"Research Competency Milestones Program of School of Medicine, CHA University School of Medicine, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Bae","family":"An","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Hyuk","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Graduate School of CHA University, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-0330","authenticated-orcid":false,"given":"Jong Joo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Graduate School, Kyung Hee University, Seoul 02453, Republic of Korea"},{"name":"Department of Neurosurgery, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul 03181, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Bum","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kyung Hee University, Seoul 02453, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Cheul","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Youn","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Graduate School of CHA University, Seongnam-si 13496, Republic of Korea"},{"name":"Department of Microbiology, School of Medicine, CHA University, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0834-9325","authenticated-orcid":false,"given":"Inbo","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"847","DOI":"10.14245\/ns.2244656.328","article-title":"Cervical facet joint degeneration","volume":"19","author":"Goel","year":"2022","journal-title":"Neurospine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"805","DOI":"10.14245\/ns.2244058.029","article-title":"Successful criteria for indirect decompression with lateral lumbar interbody fusion","volume":"19","author":"Yingsakmongkol","year":"2022","journal-title":"Neurospine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"34","DOI":"10.14245\/ns.2040454.227","article-title":"Revision surgeries at the index level after cervical disc arthroplasty\u2014A systematic review","volume":"18","author":"Joaquim","year":"2021","journal-title":"Neurospine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1007\/s00586-021-06827-y","article-title":"Effect of lumbar laminectomy on spinal sagittal alignment: A systematic review","volume":"30","author":"Hatakka","year":"2021","journal-title":"Eur. Spine J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"307","DOI":"10.14245\/ns.2040706.353","article-title":"What can legacy patient-reported outcome measures tell us about participation bias in patient-reported outcomes measurement information system scores among lumbar spine patients?","volume":"19","author":"Lynch","year":"2022","journal-title":"Neurospine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"632","DOI":"10.14245\/ns.2244366.183","article-title":"Extra cellular matrix remodeling: An adjunctive target for spinal cord injury and intervertebral disc degeneration","volume":"19","author":"Kumar","year":"2022","journal-title":"Neurospine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"393","DOI":"10.14245\/ns.2143258.629","article-title":"Prevalence and clinical impact of cervical facet joint degeneration on degenerative cervical myelopathy: A novel computed tomography classification study","volume":"19","author":"Okamoto","year":"2022","journal-title":"Neurospine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"224","DOI":"10.14245\/ns.2143084.542","article-title":"Risk factors for poor outcomes following minimally invasive discectomy: A post hoc subgroup analysis of 2-year follow-up prospective data","volume":"19","author":"Chen","year":"2022","journal-title":"Neurospine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"336","DOI":"10.14245\/ns.2040824.412","article-title":"Factors predicting the clinical outcome after trans-sacral epiduroscopic laser decompression for lumbar disc herniation","volume":"18","author":"Yoo","year":"2021","journal-title":"Neurospine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.14245\/ns.2040236.118","article-title":"Effects of body mass index on perioperative outcomes in patients undergoing anterior cervical discectomy and fusion surgery","volume":"18","author":"McCarthy","year":"2021","journal-title":"Neurospine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"574","DOI":"10.4184\/asj.2018.12.3.574","article-title":"Etiology, evaluation, and treatment of failed back surgery syndrome","volume":"12","author":"Sebaaly","year":"2018","journal-title":"Asian Spine J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1526-4637.2011.01089.x","article-title":"Failed back surgery syndrome","volume":"12","author":"Chan","year":"2011","journal-title":"Pain Med. (Malden Mass.)"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.pmr.2014.01.014","article-title":"The failed back surgery syndrome: Pitfalls surrounding evaluation and treatment","volume":"25","author":"Shapiro","year":"2014","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"130s","DOI":"10.1177\/2192568219872460","article-title":"Intervertebral disc repair: Current concepts","volume":"10","author":"Ju","year":"2020","journal-title":"Glob. Spine J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vizoso, F.J., Eiro, N., Costa, L., Esparza, P., Landin, M., Diaz-Rodriguez, P., Schneider, J., and Perez-Fernandez, R. (2019). Mesenchymal stem cells in homeostasis and systemic diseases: Hypothesis, evidences, and therapeutic opportunities. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153738"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Francos, S., Eiro, N., Costa, L.A., Escudero-Cernuda, S., Fern\u00e1ndez-S\u00e1nchez, M.L., and Vizoso, F.J. (2021). Mesenchymal stem cells as a cornerstone in a galaxy of intercellular signals: Basis for a new era of medicine. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073576"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.stemcr.2021.05.003","article-title":"Mesenchymal stromal cell-derived exosomes in cardiac regeneration and repair","volume":"16","author":"Sun","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.4252\/wjsc.v13.i1.49","article-title":"Mesenchymal stem cell-derived small extracellular vesicles in the treatment of human diseases: Progress and prospect","volume":"13","author":"Shi","year":"2021","journal-title":"World J. Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7538025","DOI":"10.1155\/2022\/7538025","article-title":"Mesenchymal stem cell-derived extracellular vesicles: Immunomodulatory effects and potential applications in intervertebral disc degeneration","volume":"2022","author":"Hu","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: Pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1186\/s13075-015-0834-8","article-title":"Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration","volume":"17","author":"Suzuki","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5601593","DOI":"10.1155\/2017\/5601593","article-title":"Ros: Crucial intermediators in the pathogenesis of intervertebral disc degeneration","volume":"2017","author":"Feng","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41413-020-00125-x","article-title":"Painful intervertebral disc degeneration and inflammation: From laboratory evidence to clinical interventions","volume":"9","author":"Lyu","year":"2021","journal-title":"Bone Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2186728","DOI":"10.1155\/2019\/2186728","article-title":"Characterization of different sources of human mscs expanded in serum-free conditions with quantification of chondrogenic induction in 3d","volume":"2019","author":"Fabre","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1036","DOI":"10.1002\/jsp2.1036","article-title":"Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ors spine section","volume":"1","author":"Smith","year":"2018","journal-title":"JOR Spine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"831","DOI":"10.24976\/Discov.Med.202335178.78","article-title":"Therapeutic effect of human bone marrow- and adipose-derived stem cells on intervertebral disc degeneration: A comparative study on rats","volume":"35","author":"Zhang","year":"2023","journal-title":"Discov. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1127303","DOI":"10.3389\/fmed.2023.1127303","article-title":"Co-regulation of sox9 and tgf\u03b21 transcription factors in mesenchymal stem cells regenerated the intervertebral disc degeneration","volume":"10","author":"Khalid","year":"2023","journal-title":"Front. Med."},{"key":"ref_28","first-page":"173","article-title":"Mesenchymal stem cells for intervertebral disc regeneration","volume":"30","author":"Russo","year":"2016","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Morita, K., Schol, J., Volleman, T.N.E., Sakai, D., Sato, M., and Watanabe, M. (2021). Screening for growth-factor combinations enabling synergistic differentiation of human msc to nucleus pulposus cell-like cells. Appl. Sci., 11.","DOI":"10.3390\/app11083673"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Russo, F., Ambrosio, L., Peroglio, M., Guo, W., Wangler, S., Gewiess, J., Grad, S., Alini, M., Papalia, R., and Vadal\u00e0, G. (2021). A hyaluronan and platelet-rich plasma hydrogel for mesenchymal stem cell delivery in the intervertebral disc: An organ culture study. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062963"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.21037\/jss.2019.09.22","article-title":"Stem cell therapy in discogenic back pain","volume":"5","author":"Barakat","year":"2019","journal-title":"J. Spine Surg."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ryu, J.S., Jeong, E.J., Kim, J.Y., Park, S.J., Ju, W.S., Kim, C.H., Kim, J.S., and Choo, Y.K. (2020). Application of mesenchymal stem cells in inflammatory and fibrotic diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218366"},{"key":"ref_33","first-page":"299","article-title":"Receptor activator of nuclear factor kappa b ligand in an experimental intervertebral disc degeneration","volume":"27","author":"Mackiewicz","year":"2009","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1089\/ten.tea.2012.0085","article-title":"Stromal cell-derived factor-1\u03b2 potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro","volume":"19","author":"Herberg","year":"2013","journal-title":"Tissue Eng. Part A"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1126\/science.7792603","article-title":"Transcriptional activation by tetracyclines in mammalian cells","volume":"268","author":"Gossen","year":"1995","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/5584_2019_459","article-title":"Advancing mesenchymal stem cell therapy with crispr\/cas9 for clinical trial studies","volume":"1247","author":"Golchin","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13287-017-0619-x","article-title":"Harvesting multipotent progenitor cells from a small sample of tonsillar biopsy for clinical applications","volume":"8","author":"Khatri","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17114","DOI":"10.1038\/s41598-017-16788-2","article-title":"Rna sequencing reveals a transcriptomic portrait of human mesenchymal stem cells from bone marrow, adipose tissue, and palatine tonsils","volume":"7","author":"Cho","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.3109\/14653249.2012.706708","article-title":"Tonsil-derived mesenchymal stromal cells: Evaluation of biologic, immunologic and genetic factors for successful banking","volume":"14","author":"Ryu","year":"2012","journal-title":"Cytotherapy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8616","DOI":"10.1038\/srep08616","article-title":"Tonsil-derived mesenchymal stem cells ameliorate ccl4-induced liver fibrosis in mice via autophagy activation","volume":"5","author":"Park","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.3892\/ijmm.2016.2536","article-title":"Myogenic differentiation potential of human tonsil-derived mesenchymal stem cells and their potential for use to promote skeletal muscle regeneration","volume":"37","author":"Park","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.3892\/etm.2013.1348","article-title":"Effects of tgf-\u03b21 and il-1\u03b2 on expression of adamts enzymes and timp-3 in human intervertebral disc degeneration","volume":"6","author":"Wang","year":"2013","journal-title":"Exp. Ther. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1016\/j.jbiomech.2014.04.046","article-title":"Modeling the role of igf-1 on extracellular matrix biosynthesis and cellularity in intervertebral disc","volume":"47","author":"Travascio","year":"2014","journal-title":"J. Biomech."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/jor.23351","article-title":"Heterodimeric bmp-2\/7 for nucleus pulposus regeneration-in vitro and ex vivo studies","volume":"35","author":"Li","year":"2017","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20509","DOI":"10.1074\/jbc.M410148200","article-title":"Fibroblast growth factor (fgf) 18 signals through fgf receptor 3 to promote chondrogenesis","volume":"280","author":"Davidson","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1089\/107632703768247377","article-title":"In vitro chondrogenesis of bone marrow-derived mesenchymal stem cells in a photopolymerizing hydrogel","volume":"9","author":"Williams","year":"2003","journal-title":"Tissue Eng."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.bbrc.2004.06.029","article-title":"Growth factor combination for chondrogenic induction from human mesenchymal stem cell","volume":"320","author":"Indrawattana","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.joca.2005.02.006","article-title":"Bmp-2 induces the expression of chondrocyte-specific genes in bovine synovium-derived progenitor cells cultured in three-dimensional alginate hydrogel","volume":"13","author":"Park","year":"2005","journal-title":"Osteoarthr. Cartil."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/S0736-0266(00)00054-1","article-title":"Chondrocytic differentiation of mesenchymal stem cells sequentially exposed to transforming growth factor-beta1 in monolayer and insulin-like growth factor-i in a three-dimensional matrix","volume":"19","author":"Worster","year":"2001","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/s11626-015-9969-9","article-title":"Igf-i induces adipose derived mesenchymal cell chondrogenic differentiation in vitro and enhances chondrogenesis in vivo","volume":"52","author":"Zhou","year":"2016","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1002\/jcb.25623","article-title":"Chondrogenesis of embryonic stem cell-derived mesenchymal stem cells induced by tgf\u03b21 and bmp7 through increased tgf\u03b2 receptor expression and endogenous tgf\u03b21 production","volume":"118","author":"Lee","year":"2017","journal-title":"J. Cell. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1634\/stemcells.2007-0039","article-title":"Robust, persistent transgene expression in human embryonic stem cells is achieved with aavs1-targeted integration","volume":"26","author":"Smith","year":"2008","journal-title":"Stem Cells (Dayt. Ohio)"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1186\/ar2459","article-title":"Human palatine tonsil: A new potential tissue source of multipotent mesenchymal progenitor cells","volume":"10","author":"Janjanin","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.spinee.2021.01.014","article-title":"Il-1\u03b2 promotes disc degeneration and inflammation through direct injection of intervertebral disc in a rat lumbar disc herniation model","volume":"21","author":"Kim","year":"2021","journal-title":"Spine J. Off. J. N. Am. Spine Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"R165","DOI":"10.1186\/ar3485","article-title":"The rat intervertebral disk degeneration pain model: Relationships between biological and structural alterations and pain","volume":"13","author":"Kim","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Bhujel, B., Yang, S.S., Kim, H.R., Kim, S.B., Min, B.H., Choi, B.H., and Han, I. (2023). An injectable engineered cartilage gel improves intervertebral disc repair in a rat nucleotomy model. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043146"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1002\/jor.22833","article-title":"Assessment of functional and behavioral changes sensitive to painful disc degeneration","volume":"33","author":"Lai","year":"2015","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"284","DOI":"10.3389\/fnmol.2017.00284","article-title":"Methods used to evaluate pain behaviors in rodents","volume":"10","author":"Deuis","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ohnishi, T., Sudo, H., Iwasaki, K., Tsujimoto, T., Ito, Y.M., and Iwasaki, N. (2016). In vivo mouse intervertebral disc degeneration model based on a new histological classification. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160486"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/jor.23637","article-title":"Histological and reference system for the analysis of mouse intervertebral disc","volume":"36","author":"Tam","year":"2018","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jcm.2017.11.006","article-title":"Intervertebral disk nutrients and transport mechanisms in relation to disk degeneration: A narrative literature review","volume":"17","year":"2018","journal-title":"J. Chiropr. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1097\/00007632-200206150-00007","article-title":"Increased nerve and blood vessel ingrowth associated with proteoglycan depletion in an ovine anular lesion model of experimental disc degeneration","volume":"27","author":"Melrose","year":"2002","journal-title":"Spine"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Urban, J.P.G., and Fairbank, J.C.T. (2020). Current perspectives on the role of biomechanical loading and genetics in development of disc degeneration and low back pain; a narrative review. J. Biomech., 102.","DOI":"10.1016\/j.jbiomech.2019.109573"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10499","DOI":"10.18632\/aging.102472","article-title":"Melatonin modulates il-1\u03b2-induced extracellular matrix remodeling in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration and inflammation","volume":"11","author":"Zhang","year":"2019","journal-title":"Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e1081","DOI":"10.1002\/jsp2.1081","article-title":"The transcription factors regulating intervertebral disc development","volume":"3","author":"Nakamichi","year":"2020","journal-title":"JOR Spine"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13287-016-0337-9","article-title":"Angiopoietin-1 receptor tie2 distinguishes multipotent differentiation capability in bovine coccygeal nucleus pulposus cells","volume":"7","author":"Tekari","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/ncomms2226","article-title":"Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc","volume":"3","author":"Sakai","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1089\/ten.tea.2020.0346","article-title":"Implantation of human-induced pluripotent stem cell-derived cartilage in bone defects of mice","volume":"27","author":"Iimori","year":"2021","journal-title":"Tissue Eng. Part A"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"37360","DOI":"10.1038\/srep37360","article-title":"Acidic ph promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target","volume":"6","author":"Gilbert","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1111\/j.1582-4934.2008.00657.x","article-title":"Mesenchymal stem cells induce a weak immune response in the rat striatum after allo or xenotransplantation","volume":"13","author":"Rossignol","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_71","first-page":"1167","article-title":"Transplants of human mesenchymal stem cells improve functional recovery after spinal cord injury in the rat","volume":"26","author":"Rosocha","year":"2006","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1089\/ten.tea.2009.0401","article-title":"Xenotransplantation of human mesenchymal stem cells into immunocompetent rats for calvarial bone repair","volume":"16","author":"Chuang","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Xing, H., Zhang, Z., Mao, Q., Wang, C., Zhou, Y., Zhou, X., Ying, L., Xu, H., Hu, S., and Zhang, N. (2021). Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration. J. Nanobiotechnol., 19.","DOI":"10.1186\/s12951-021-00991-5"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"R45","DOI":"10.1186\/ar2198","article-title":"Accelerated cellular senescence in degenerate intervertebral discs: A possible role in the pathogenesis of intervertebral disc degeneration","volume":"9","author":"Freemont","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1089\/dna.2016.3230","article-title":"The paracrine effect of degenerated disc cells on healthy human nucleus pulposus cells is mediated by mapk and nf-\u03bab pathways and can be reduced by tgf-\u03b21","volume":"36","author":"Cai","year":"2017","journal-title":"DNA Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e1014","DOI":"10.1002\/jsp2.1014","article-title":"Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model","volume":"1","author":"Lai","year":"2018","journal-title":"JOR Spine"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.joca.2015.09.019","article-title":"Aging and age related stresses: A senescence mechanism of intervertebral disc degeneration","volume":"24","author":"Wang","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, Y., Che, M., Xin, J., Zheng, Z., Li, J., and Zhang, S. (2020). The role of il-1\u03b2 and tnf-\u03b1 in intervertebral disc degeneration. Biomed. Pharmacother. = Biomed. Pharmacother., 131.","DOI":"10.1016\/j.biopha.2020.110660"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2958584","DOI":"10.1155\/2021\/2958584","article-title":"Cgrp regulates nucleus pulposus cell apoptosis and inflammation via the mapk\/nf-\u03bab signaling pathways during intervertebral disc degeneration","volume":"2021","author":"Sun","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/jor.1100140503","article-title":"Autocrine\/paracrine mechanism of insulin-like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs","volume":"14","author":"Osada","year":"1996","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/00007632-199103000-00001","article-title":"Stimulation of mature canine intervertebral disc by growth factors","volume":"16","author":"Thompson","year":"1991","journal-title":"Spine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.reth.2021.12.001","article-title":"Mesenchymal stem cell extracellular vesicles-derived microrna-194-5p delays the development of intervertebral disc degeneration by targeting traf6","volume":"19","author":"Sun","year":"2022","journal-title":"Regen. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"133","DOI":"10.7150\/ijbs.10598","article-title":"Adipose-derived stromal cells protect intervertebral disc cells in compression: Implications for stem cell regenerative disc therapy","volume":"11","author":"Sun","year":"2015","journal-title":"Int. J. Biol. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1097\/01.brs.0000219946.25103.db","article-title":"Exposure of the nucleus pulposus to the outside of the anulus fibrosus induces nerve injury and regeneration of the afferent fibers innervating the lumbar intervertebral discs in rats","volume":"31","author":"Inoue","year":"2006","journal-title":"Spine"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/s00586-008-0752-4","article-title":"Resolving discogenic pain","volume":"17","author":"Takahashi","year":"2008","journal-title":"Eur. Spine J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4103\/2278-0521.151403","article-title":"Novel treatment strategies for intervertebral disc degeneration","volume":"4","author":"Rizvi","year":"2015","journal-title":"Saudi J. Health Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1111\/jcmm.12268","article-title":"Painful, degenerating intervertebral discs up-regulate neurite sprouting and cgrp through nociceptive factors","volume":"18","author":"Krock","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00109-018-1712-z","article-title":"Propionibacterium acnes induces discogenic low back pain via stimulating nucleus pulposus cells to secrete pro-algesic factor of il-8\/cinc-1 through tlr2-nf-\u03bab p65 pathway","volume":"97","author":"Jiao","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2217\/rme-2016-0069","article-title":"Strategies in regenerative medicine for intervertebral disc repair using mesenchymal stem cells and bioscaffolds","volume":"11","author":"Melrose","year":"2016","journal-title":"Regen. Med."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Cunha, C., Leite Pereira, C., Ferreira, J.R., Ribeiro-Machado, C., Grad, S., Santos, S.G., and Gon\u00e7alves, R.M. (2021). Therapeutic strategies for ivd regeneration through hyaluronan\/sdf-1-based hydrogel and intravenous administration of mscs. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179609"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Ha, D.H., Kim, H.K., Lee, J., Kwon, H.H., Park, G.H., Yang, S.H., Jung, J.Y., Choi, H., Lee, J.H., and Sung, S. (2020). Mesenchymal stem\/stromal cell-derived exosomes for immunomodulatory therapeutics and skin regeneration. Cells, 9.","DOI":"10.3390\/cells9051157"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nbt.1562","article-title":"Efficient targeting of expressed and silent genes in human escs and ipscs using zinc-finger nucleases","volume":"27","author":"Hockemeyer","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Heo, C.H., Roh, E.J., Kim, J., Choi, H., Jang, H.Y., Lee, G., Lim, C.S., and Han, I. (2023). Development of a cox-2-selective fluorescent probe for the observation of early intervertebral disc degeneration. J. Funct. Biomater., 14.","DOI":"10.3390\/jfb14040192"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Choi, U.Y., Joshi, H.P., Payne, S., Kim, K.T., Kyung, J.W., Choi, H., Cooke, M.J., Kwon, S.Y., Roh, E.J., and Sohn, S. (2020). An injectable hyaluronan-methylcellulose (hamc) hydrogel combined with wharton\u2019s jelly-derived mesenchymal stromal cells (wj-mscs) promotes degenerative disc repair. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197391"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2101483","DOI":"10.1002\/adhm.202101483","article-title":"Local delivery of senolytic drug inhibits intervertebral disc degeneration and restores intervertebral disc structure","volume":"11","author":"Lim","year":"2022","journal-title":"Adv. Healthc. Mater."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e1150","DOI":"10.1002\/jsp2.1150","article-title":"Development of a standardized histopathology scoring system for intervertebral disc degeneration in rat models: An initiative of the ors spine section","volume":"4","author":"Lai","year":"2021","journal-title":"JOR Spine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16024\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:18:36Z","timestamp":1760131116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,7]]},"references-count":96,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216024"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216024","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,7]]}}}