{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:55:01Z","timestamp":1790603701991,"version":"4.1.0"},"reference-count":337,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"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. Immunol."],"abstract":"<jats:p>Ageing remodels the neuroimmune, metabolic, and vascular environment in ways that accelerate neuronal vulnerability and constrain tissue repair. Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) are therefore attractive candidates for neurodegenerative disorders because their effects extend beyond cell replacement to coordinated paracrine, immunomodulatory, trophic, and vascular regulation. This critical review evaluates the biological rationale, disease-specific evidence, translational limitations, and precision-development strategies for MSC-based interventions in Alzheimer\u2019s disease, Parkinson\u2019s disease, Huntington\u2019s disease, amyotrophic lateral sclerosis, multiple system atrophy, and vascular dementia, whilst using selected rare hereditary neurodegenerative disorders as exploratory boundary cases. Current evidence supports three interconnected modes of action: reprogramming maladaptive neuroimmune responses; preserving neuronal homeostasis through trophic support, mitochondrial rescue, and proteostasis regulation; and restoring the neurovascular unit and blood-brain barrier. However, reproducible clinical efficacy remains limited by variation in tissue source, donor age, manufacturing, potency, dose, route, and outcome selection, as well as poor central nervous system exposure and inadequate patient stratification. Ageing-related changes in both the recipient microenvironment and the cellular product further complicate translation. Future development should replace empirical cell administration with mechanism-defined products, validated potency assays, quantitative biodistribution, biomarker-guided enrolment, engineered cells or vesicles, rational combinations, and trials using disease-modifying endpoints. MSC-based therapies are best positioned not as universal regenerative agents, but as mechanism-defined, biomarker-matched products\u2014potentially engineered at the cell or EV level\u2014that regulate biologically active and potentially reversible disease states.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1965598","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:56:41Z","timestamp":1790600201000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal stromal cells in age-related neurodegenerative disorders: mechanisms, translational barriers, and precision strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhiyong","family":"Long","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, The Affiliated Panyu Central Hospital of Guangzhou Medical University","place":["Guangzhou, 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