{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T07:49:53Z","timestamp":1782892193136,"version":"3.54.5"},"reference-count":476,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis\/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1742864","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T06:30:50Z","timestamp":1771828250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mesenchymal stem cells and the central nervous system: historical perspectives and future directions"],"prefix":"10.3389","volume":"19","author":[{"given":"Christopher Y.","family":"Mazurek","sequence":"first","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia K.","family":"Kaniuk","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Ahuja","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Northwestern Medicine","place":["Chicago, IL, United States"]},{"name":"Simpson-Querrey Research Institute","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1182\/blood-2004-04-1559","article-title":"Human mesenchymal stem cells modulate allogeneic immune cell responses.","volume":"105","author":"Aggarwal","year":"2005","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"11658","DOI":"10.1038\/s41598-021-91291-3","article-title":"Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines.","volume":"11","author":"Ahmadvand Koohsari","year":"2021","journal-title":"Sci. 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