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Therapies involving mesenchymal stromal cells (MSCs) have attracted substantial attention as a potential clinical therapeutic strategy across chronic central nervous system (CNS) disorders, due to their multifaceted ability to modulate immune response and confer neuroprotection. While initially explored for their multilineage differentiation potential, MSCs are now predominantly recognized for their paracrine functions, including secretion of soluble factors and extracellular vesicles. These acellular mediators induce diverse neuroprotective effects by attenuating neuroinflammation, stabilizing the blood\u2013brain barrier, reprogramming glial and lymphocyte activity, and delivering regulatory microRNAs that modulate neuronal apoptosis and inflammatory gene networks. In this review, we summarize molecular evidence from in vitro and in vivo preclinical models, and early clinical investigations that demonstrate how tissue source and immunobiological plasticity shape the efficacy of MSCs. We further highlight emerging trends toward acellular MSC-derived therapies, offering a mechanistically versatile platform for therapeutic interventions for common neurodegenerative and neuroinflammatory disorders of the CNS, particularly Alzheimer\u2019s disease, Parkinson\u2019s disease and multiple sclerosis, a primary autoimmune demyelinating disorder.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1186\/s40035-026-00554-4","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T02:23:06Z","timestamp":1779070986000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mesenchymal stromal cells and neuroinflammation: a multimodal approach to neuroprotection and future therapeutic horizons"],"prefix":"10.1186","volume":"15","author":[{"given":"Alexandro Angelo","family":"Bufi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1229-9671","authenticated-orcid":false,"given":"Andrea","family":"Papait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ponsaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta Rosa","family":"Silini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Parolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"issue":"6","key":"554_CR1","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1093\/geront\/gnv130","volume":"55","author":"EM Crimmins","year":"2015","unstructured":"Crimmins EM. 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