{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:06:47Z","timestamp":1790644007971,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006541","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["PIPF-2024\/SAL-GL-34334 and PIPF\/SAL-GL-34708."],"award-info":[{"award-number":["PIPF-2024\/SAL-GL-34334 and PIPF\/SAL-GL-34708."]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), characterised by inflammation, demyelination, and progressive neurodegeneration. Although current disease-modifying therapies (DMTs) can reduce relapse rates and inflammatory activity, they rarely stop long-term progression or repair neurological damage. In recent years, cell-based therapies have emerged as promising approaches to promote immune regulation and neuroregeneration in MS. Methods: This review summarises the current clinical evidence from studies in humans investigating cell-based treatments for MS, including autologous haematopoietic stem cell transplantation (AHSCT), mesenchymal stem cells (MSCs), and neural stem or progenitor cells (NSCs). A systematic literature search was performed using PubMed, Scopus, and ClinicalTrials.gov, focusing on human clinical trials that met specific inclusion criteria. Results: Prevailing findings show that AHSCT provides the most consistent benefit, achieving long-term immune reconstitution and remission in patients with highly active relapsing\u2013remitting MS (RRMS), although it carries procedural risks. MSC therapies have demonstrated good safety and biological activity, especially when delivered intrathecally (IT) in progressive MS, though clinical results remain variable. Conclusions: NSC-based treatments are still at an early stage of clinical research but show potential for CNS repair. The main limitations across studies include differences in protocols, small sample sizes, and short follow-up periods. Further large-scale, randomised controlled trials are needed to confirm long-term efficacy, define optimal delivery methods, and establish standardised clinical protocols.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010030","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:50:21Z","timestamp":1766710221000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cell Therapy in Multiple Sclerosis: Clinical Advances, Limitations, and Future Perspectives from Clinical Studies\u2014A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-438X","authenticated-orcid":false,"given":"Ola","family":"Mohamed Fathy Kamal","sequence":"first","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Servicio de Medicina F\u00edsica y Rehabilitaci\u00f3n, Hospital Central de la Defensa, 28047 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-8019","authenticated-orcid":false,"given":"Doddy Denise","family":"Ojeda-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-5558","authenticated-orcid":false,"given":"Bel\u00e9n","family":"Selma-Calvo","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8007-3586","authenticated-orcid":false,"given":"Marina","family":"Garc\u00eda-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4843-324X","authenticated-orcid":false,"given":"Mar\u00eda Teresa","family":"Larriba-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6087-3892","authenticated-orcid":false,"given":"Lucia","family":"Martin-Blanco","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5520-2708","authenticated-orcid":false,"given":"Jordi A.","family":"Matias-Guiu","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Servicio de Neurolog\u00eda, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-9043","authenticated-orcid":false,"given":"Jorge","family":"Matias-Guiu","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"},{"name":"Servicio de Neurolog\u00eda, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3097-5557","authenticated-orcid":false,"given":"Ulises","family":"Gomez-Pinedo","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurobiolog\u00eda y Terapias Avanzadas, Instituto de Neurociencias, Instituto de Investigaci\u00f3n Sanitaria San Carlos (IdISSC), Hospital Cl\u00ednico San Carlos, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","unstructured":"(2025, March 28). Multiple Sclerosis\u2014ClinicalKey. Available online: https:\/\/www-clinicalkey-es.m-husc.a17.csinet.es\/#!\/content\/clinical_overview\/67-s2.0-3a8d3d82-9370-4097-98da-960ee9016f2e#treatment-heading-31."},{"key":"ref_2","first-page":"33","article-title":"Multiple Sclerosis Diagnosis and Management: A simple Literature Review","volume":"10","author":"Alshammari","year":"2019","journal-title":"Arch. Pharm. Pract."},{"key":"ref_3","unstructured":"(2025, March 28). Consensus Statement of the Spanish Society of Neurology on the Treatment of Multiple Sclerosis and Holistic Patient Management in 2023\u2014ClinicalKey. Available online: https:\/\/www-clinicalkey-es.m-husc.a17.csinet.es\/#!\/content\/journal\/1-s2.0-S2173580824000191."},{"key":"ref_4","first-page":"e33242","article-title":"An Overview of the History, Pathophysiology, and Pharmacological Interventions of Multiple Sclerosis","volume":"15","author":"Dighriri","year":"2023","journal-title":"Cureus"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1177\/1352458517751049","article-title":"ECTRIMS\/EAN Guideline on the pharmacological treatment of people with multiple sclerosis","volume":"24","author":"Montalban","year":"2018","journal-title":"Mult. Scler. J."},{"key":"ref_6","unstructured":"(2025, March 28). Evaluation and Diagnosis of Multiple Sclerosis in Adults\u2014UpToDate. Available online: https:\/\/www-uptodate-com.m-husc.a17.csinet.es\/contents\/evaluation-and-diagnosis-of-multiple-sclerosis-in-adults\/print?search=multiple%20sclerosis&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e37297","DOI":"10.1097\/MD.0000000000037297","article-title":"Review of multiple sclerosis: Epidemiology, etiology, pathophysiology, and treatment","volume":"103","author":"Haki","year":"2024","journal-title":"Medicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.amjmed.2020.05.049","article-title":"Treatment of Multiple Sclerosis: A Review","volume":"133","author":"Hauser","year":"2020","journal-title":"Am. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Marrie, R.A., Fisk, J.D., Fitzgerald, K., Kowalec, K., Maxwell, C., Rotstein, D., Salter, A., and Tremlett, H. (2023). Etiology, effects and management of comorbidities in multiple sclerosis: Recent advances. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1197195"},{"key":"ref_10","unstructured":"(2025, March 28). Manifestations of Multiple Sclerosis in Adults\u2014UpToDate. Available online: https:\/\/www-uptodate-com.m-husc.a17.csinet.es\/contents\/manifestations-of-multiple-sclerosis-in-adults\/print?search=multiple%20sclerosis&topicRef=1688&source=see_link."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Muguruza, E., Villar-G\u00f3mez, N., Matias-Guiu, J.A., Selma-Calvo, B., Moreno, L., Sancho-Bielsa, F., L\u00f3pez-Carbonero, J.I., Benito-Martin, M.S., Garc\u00eda-Flores, S., and Bonel-Garc\u00eda, N. (2022). The Integration of Cell Therapy and Biomaterials as Treatment Strategies for Remyelination. Life, 12.","DOI":"10.3390\/life12040474"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S1474-4422(21)00063-6","article-title":"Cellular immunology of relapsing multiple sclerosis: Interactions, checks, and balances","volume":"20","author":"Li","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sun, X., Zhang, F., Wang, L., Lee, G., Yang, S., Zhou, D., Chang, B., Hu, B., and Zhou, Y. (2025). Immunological microenvironment and targeted therapeutics in multiple sclerosis: New insights in crosstalk between immune niches and CNS. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1604987"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103480","DOI":"10.1016\/j.autrev.2023.103480","article-title":"Current knowledge on multiple sclerosis pathophysiology, disability progression assessment and treatment options, and the role of autologous hematopoietic stem cell transplantation","volume":"23","author":"Gakis","year":"2024","journal-title":"Autoimmun. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5105","DOI":"10.1523\/JNEUROSCI.2840-19.2020","article-title":"Regulatory B Cells Normalize CNS Myeloid Cell Content in a Mouse Model of Multiple Sclerosis and Promote Oligodendrogenesis and Remyelination","volume":"40","author":"Pennati","year":"2020","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8570","DOI":"10.1038\/s41467-024-52444-w","article-title":"CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents","volume":"15","author":"Wagstaff","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s12035-013-8543-2","article-title":"Therapeutic effect of transplanted human Wharton\u2019s jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) in an animal model of multiple sclerosis","volume":"49","author":"Parivar","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41407","DOI":"10.1038\/srep41407","article-title":"Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model","volume":"7","author":"Fan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"146615","DOI":"10.1016\/j.brainres.2019.146615","article-title":"The neural stem cell secretome and its role in brain repair","volume":"1729","author":"Willis","year":"2020","journal-title":"Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nature01552","article-title":"Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis","volume":"422","author":"Pluchino","year":"2003","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/nature03889","article-title":"Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism","volume":"436","author":"Pluchino","year":"2005","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Smith, J.A., Nicaise, A.M., Ionescu, R.-B., Hamel, R., Peruzzotti-Jametti, L., and Pluchino, S. (2021). Stem Cell Therapies for Progressive Multiple Sclerosis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.696434"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"He, J., Huang, Y., Liu, J., Lan, Z., Tang, X., and Hu, Z. (2021). The Efficacy of Mesenchymal Stem Cell Therapies in Rodent Models of Multiple Sclerosis: An Updated Systematic Review and Meta-Analysis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.711362"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kr\u00e5kenes, T., Sandvik, C.E., Ytterdal, M., Gavasso, S., Evjenth, E.C., B\u00f8, L., and Kvistad, C.E. (2024). The Therapeutic Potential of Exosomes from Mesenchymal Stem Cells in Multiple Sclerosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910292"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113895","DOI":"10.1016\/j.expneurol.2021.113895","article-title":"Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system","volume":"347","author":"Zhang","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121949","DOI":"10.1016\/j.biomaterials.2022.121949","article-title":"Exosomes based strategies for brain drug delivery","volume":"293","author":"Rehman","year":"2023","journal-title":"Biomaterials"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Spinelli, S., Tripodi, D., Corti, N., Zocchi, E., Bruschi, M., Leoni, V., and Dominici, R. (2025). Roles, Functions, and Pathological Implications of Exosomes in the Central Nervous System. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031345"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105487","DOI":"10.1016\/j.jbc.2023.105487","article-title":"Exosomal miR-23a-3p derived from human umbilical cord mesenchymal stem cells promotes remyelination in central nervous system demyelinating diseases by targeting Tbr1\/Wnt pathway","volume":"300","author":"Qin","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1136\/jnnp-2018-319446","article-title":"Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis","volume":"90","author":"Moore","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/5584_2018_247","article-title":"Stem Cell Therapy for Multiple Sclerosis","volume":"Volume 1084","author":"Genc","year":"2019","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wens, I., Janssens, I., Derdelinckx, J., Meena, M., Willekens, B., and Cools, N. (2021). Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147536"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3937","DOI":"10.1007\/s00415-022-11063-5","article-title":"The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis","volume":"269","author":"Willison","year":"2022","journal-title":"J. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Abbasi-Kangevari, M., Ghamari, S.-H., Safaeinejad, F., Bahrami, S., and Niknejad, H. (2019). Potential Therapeutic Features of Human Amniotic Mesenchymal Stem Cells in Multiple Sclerosis: Immunomodulation, Inflammation Suppression, Angiogenesis Promotion, Oxidative Stress Inhibition, Neurogenesis Induction, MMPs Regulation, and Remyelination Stimulation. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00238"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"116830","DOI":"10.1016\/j.lfs.2019.116830","article-title":"The potential use of mesenchymal stem cells for the treatment of multiple sclerosis","volume":"235","author":"Mansoor","year":"2019","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1515\/revneuro-2022-0102","article-title":"Current advances in stem cell therapy in the treatment of multiple sclerosis","volume":"34","author":"Moradi","year":"2023","journal-title":"Rev. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S1474-4422(11)70121-1","article-title":"Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases","volume":"10","author":"Uccelli","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1038\/s41423-020-00618-z","article-title":"Paving the way towards an effective treatment for multiple sclerosis: Advances in cell therapy","volume":"18","author":"Mansilla","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Islam, M.A., Alam, S.S., Kundu, S., Ahmed, S., Sultana, S., Patar, A., and Hossan, T. (2023). Mesenchymal Stem Cell Therapy in Multiple Sclerosis: A Systematic Review and Meta-Analysis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12196311"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.1093\/brain\/awaa333","article-title":"Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis","volume":"143","author":"Petrou","year":"2020","journal-title":"Brain J. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gugliandolo, A., Bramanti, P., and Mazzon, E. (2020). Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Pre-Clinical to Clinical Studies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228662"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s13287-024-03765-6","article-title":"Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: Results from a phase II, randomized, placebo-controlled clinical trial","volume":"15","author":"Harris","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rossi, B., Virla, F., Angelini, G., Scambi, I., Bani, A., Marostica, G., Caprioli, M., Anni, D., Furlan, R., and Marzola, P. (2025). Intranasal Administration of Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Has Therapeutic Effect in Experimental Autoimmune Encephalomyelitis. Cells, 14.","DOI":"10.3390\/cells14151172"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dadfar, S., Yazdanpanah, E., Pazoki, A., Nemati, M.H., Eslami, M., Haghmorad, D., and Oksenych, V. (2024). The Role of Mesenchymal Stem Cells in Modulating Adaptive Immune Responses in Multiple Sclerosis. Cells, 13.","DOI":"10.3390\/cells13181556"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sheikhi, K., Ghaderi, S., Firouzi, H., Rahimibarghani, S., Shabani, E., Afkhami, H., and Yarahmadi, A. (2025). Recent advances in mesenchymal stem cell therapy for multiple sclerosis: Clinical applications and challenges. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1517369"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hasan, A., Deeb, G., Rahal, R., Atwi, K., Mondello, S., Marei, H.E., Gali, A., and Sleiman, E. (2017). Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00028"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Santos, S.I.P., Ortiz-Pe\u00f1uela, S.J., de Paula Filho, A., Tomiyama, A.L.M.R., Coser, L.d.O., da Silveira, J.C., Martins, D.D.S., Ciena, A.P., de Oliveira, A.L.R., and Ambr\u00f3sio, C.E. (2024). Oligodendrocyte precursor cell-derived exosomes combined with cell therapy promote clinical recovery by immunomodulation and gliosis attenuation. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1413843"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1007\/s12035-017-0566-7","article-title":"Neural Stem Cell-Based Regenerative Approaches for the Treatment of Multiple Sclerosis","volume":"55","author":"Xiao","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.1093\/brain\/awac307","article-title":"Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: The more, the merrier?","volume":"145","author":"Lubetzki","year":"2022","journal-title":"Brain J. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1093\/brain\/awx154","article-title":"Cell-based therapeutic strategies for multiple sclerosis","volume":"140","author":"Scolding","year":"2017","journal-title":"Brain J. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"122807","DOI":"10.1016\/j.biomaterials.2024.122807","article-title":"Multiple sclerosis treatments a review of current biomedical engineering approaches","volume":"313","author":"Mohseni","year":"2025","journal-title":"Biomaterials"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hijal, N., Fouani, M., and Awada, B. (2024). Unveiling the fate and potential neuroprotective role of neural stem\/progenitor cells in multiple sclerosis. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1438404"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Pinedo, U., Mat\u00edas-Guiu, J.A., Ojeda-Hernandez, D., de la Fuente-Martin, S., Kamal, O.M.-F., Benito-Martin, M.S., Selma-Calvo, B., Montero-Escribano, P., and Mat\u00edas-Guiu, J. (2023). In Vitro Effects of Methylprednisolone over Oligodendroglial Cells: Foresight to Future Cell Therapies. Cells, 12.","DOI":"10.3390\/cells12111515"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"eadk9918","DOI":"10.1126\/sciadv.adk9918","article-title":"Injectable shear-thinning hydrogels promote oligodendrocyte progenitor cell survival and remyelination in the central nervous system","volume":"10","author":"Mohamed","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"24098","DOI":"10.1038\/s41598-024-75956-3","article-title":"Unveiling the Immunomodulatory and regenerative potential of iPSC-derived mesenchymal stromal cells and their extracellular vesicles","volume":"14","author":"Buitrago","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9283","DOI":"10.3390\/ijms16059283","article-title":"Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis","volume":"16","author":"Xiao","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Allegretta, C., D\u2019Amico, E., Manuti, V., Avolio, C., and Conese, M. (2022). Mesenchymal Stem Cell-Derived Extracellular Vesicles and Their Therapeutic Use in Central Nervous System Demyelinating Disorders. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073829"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"114674","DOI":"10.1016\/j.expneurol.2023.114674","article-title":"Harnessing the therapeutic potential of mesenchymal stem\/stromal cell-derived extracellular vesicles as a novel cell-free therapy for animal models of multiple sclerosis","volume":"373","author":"Jafarinia","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref_60","unstructured":"(2012, August 20). Stem Cell Therapy for Patients with Multiple Sclerosis Failing Alternate Approved Therapy\u2014A Randomized Study. ClinicalTrials.gov Identifier: NCT00273364, Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT00273364."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kalincik, T., Sharmin, S., Roos, I., Freedman, M.S., Atkins, H., Massey, J., Sutton, I., Withers, B., Burman, J., and Torkildsen, \u00d8. (2025). Haematopoietic stem cell transplant versus immune-reconstitution therapy in relapsing multiple sclerosis. Brain J. Neurol., awaf286.","DOI":"10.1093\/brain\/awaf286"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1001\/jamaneurol.2023.1184","article-title":"Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis","volume":"80","author":"Kalincik","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"45","DOI":"10.18620\/ctt-1866-8836-2021-10-2-45-53","article-title":"Autologous hematopoietic stem cell transplantation with low-intensity conditioning regimens in relapsing remitting multiple sclerosis: Clinical outcomes and quality of life","volume":"10","author":"Melnichenko","year":"2021","journal-title":"Cell. Ther. Transplant."},{"key":"ref_64","unstructured":"Burt, R.K. (2025, October 16). Maximizing Outcome of Multiple Sclerosis Transplantation (MOST). ClinicalTrials.gov Identifier: NCT03342638, Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT03342638."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1111\/bjh.20199","article-title":"Autologous haematopoietic stem cell transplantation for multiple sclerosis in the UK: A 20-year retrospective analysis of activity and haematological outcomes from the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT)","volume":"207","author":"Kazmi","year":"2025","journal-title":"Br. J. Haematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1136\/jnnp-2022-328797","article-title":"Impact of previous disease-modifying treatment on safety and efficacy in patients with MS treated with AHSCT","volume":"93","author":"Kvistad","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1111\/ene.15280","article-title":"Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary-progressive multiple sclerosis","volume":"29","author":"Mariottini","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1177\/13524585251349129","article-title":"Aggressive MS and Autologous HSCT: A review on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation","volume":"31","author":"Boffa","year":"2025","journal-title":"Mult. Scler. Houndmills Basingstoke Engl."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s41582-024-01050-x","article-title":"Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis and neuromyelitis optica spectrum disorder\u2014Recommendations from ECTRIMS and the EBMT","volume":"21","author":"Muraro","year":"2025","journal-title":"Nat. Rev. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S1474-4422(21)00301-X","article-title":"Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): A phase 2, randomised, double-blind crossover trial","volume":"20","author":"Uccelli","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.clinph.2022.01.125","article-title":"Neurophysiological outcomes following mesenchymal stem cell therapy in multiple sclerosis","volume":"136","author":"Tremblay","year":"2022","journal-title":"Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol."},{"key":"ref_72","unstructured":"Hope Biosciences Stem Cell Research Foundation (2025, September 26). Randomized Double-Blind Phase 2: Efficacy and Safety of Autologous HB-MSCs vs. Placebo for Treatment of Multiple Sclerosis. ClinicalTrials.gov identifier NCT05116540, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05116540?term=NCT05116540&rank=1."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"16005","DOI":"10.1038\/s41598-025-00590-6","article-title":"Cell therapy with placenta-derived mesenchymal stem cells for secondary progressive multiple sclerosis patients in a phase 1 clinical trial","volume":"15","author":"Shokati","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e928","DOI":"10.1212\/NXI.0000000000000928","article-title":"Mesenchymal stem cell-derived neural progenitors in progressive MS: Two-year follow-up of a phase I study","volume":"8","author":"Harris","year":"2021","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/stcltm\/szab017","article-title":"Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis","volume":"11","author":"Petrou","year":"2022","journal-title":"Stem Cells Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"578613","DOI":"10.1016\/j.jneuroim.2025.578613","article-title":"Kinetics of serum NFL and GFAP and changes in cognitive functions, in MS patients treated with repeated administrations of autologous mesenchymal stem cells (MSC-NG01)","volume":"403","author":"Petrou","year":"2025","journal-title":"J. Neuroimmunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1177\/13524585221122156","article-title":"Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis","volume":"29","author":"Cohen","year":"2023","journal-title":"Mult. Scler. Houndmills Basingstoke Engl."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Petrou, P., Kassis, I., Ginzberg, A., Halimi, M., Yaghmour, N., Abramsky, O., and Karussis, D. (2021). Long-Term Clinical and Immunological Effects of Repeated Mesenchymal Stem Cell Injections in Patients With Progressive Forms of Multiple Sclerosis. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.639315"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"9636897241233045","DOI":"10.1177\/09636897241233045","article-title":"Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Multiple Sclerosis Patients: Phase I\/II Dose-Finding Clinical Study","volume":"33","author":"Jamali","year":"2024","journal-title":"Cell Transplant."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Amoriello, R., Greiff, V., Aldinucci, A., Bonechi, E., Carnasciali, A., Peruzzi, B., Repice, A.M., Mariottini, A., Saccardi, R., and Mazzanti, B. (2020). The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00559"},{"key":"ref_81","first-page":"47","article-title":"Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study","volume":"35","author":"Chwojnicki","year":"2021","journal-title":"BioDrugs Clin. Immunother. Biopharm. Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"103782","DOI":"10.1016\/j.msard.2022.103782","article-title":"Repeat infusion of autologous bone marrow cells in progressive multiple sclerosis\u2014A phase I extension study (SIAMMS II)","volume":"61","author":"Rice","year":"2022","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41591-022-02097-3","article-title":"Neural stem cell transplantation in patients with progressive multiple sclerosis: An open-label, phase 1 study","volume":"29","author":"Genchi","year":"2023","journal-title":"Nat. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.stem.2023.11.001","article-title":"Phase I clinical trial of intracerebroventricular transplantation of allogeneic neural stem cells in people with progressive multiple sclerosis","volume":"30","author":"Leone","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/jnr.25129","article-title":"Cell-based experimental strategies for myelin repair in multiple sclerosis","volume":"101","author":"Borda","year":"2023","journal-title":"J. Neurosci. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"12545","DOI":"10.1038\/s41598-024-62726-4","article-title":"Efficacy and safety of stem cell transplantation for multiple sclerosis: A systematic review and meta-analysis of randomized controlled trials","volume":"14","author":"Nawar","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.vhri.2020.10.008","article-title":"Impact of Immunoablation and Autologous Hematopoietic Stem Cell Transplantation on Treatment Cost of Multiple Sclerosis: Real-World Nationwide Study","volume":"25","author":"Orlewska","year":"2021","journal-title":"Value Health Reg. Issues"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1001\/jamaneurol.2024.3818","article-title":"Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology: A Review","volume":"82","author":"Ismail","year":"2025","journal-title":"JAMA Neurol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.actbio.2024.09.002","article-title":"Thermosensitive chitosan-based hydrogel: A vehicle for overcoming the limitations of nose-to-brain cell therapy","volume":"188","author":"Fraile","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S1474-4422(22)00117-X","article-title":"Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): A first-in-human, open-label intervention study","volume":"21","author":"Baak","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Ojeda-Hern\u00e1ndez, D.D., Hern\u00e1ndez-Sapi\u00e9ns, M.A., Reza-Zald\u00edvar, E.E., Canales-Aguirre, A., Mat\u00edas-Guiu, J.A., Mat\u00edas-Guiu, J., Mateos-D\u00edaz, J.C., G\u00f3mez-Pinedo, U., and Sancho-Bielsa, F. (2022). Exosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis. Life, 12.","DOI":"10.3390\/life12091417"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1080\/00207454.2022.2042690","article-title":"Opportunities and challenges: Mesenchymal stem cells in the treatment of multiple sclerosis","volume":"133","author":"Zhang","year":"2023","journal-title":"Int. J. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"467","DOI":"10.7326\/M18-0850","article-title":"PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation","volume":"169","author":"Tricco","year":"2018","journal-title":"Ann. Intern. Med."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/1\/30\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:25:50Z","timestamp":1767072350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/1\/30"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,25]]},"references-count":93,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["pharmaceutics18010030"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18010030","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,25]]}}}