Mesenchymal stromal cells and paracrine modulation of neuroplasticity in the central nervous system

Abstract

Mesenchymal stromal cells (MSCs) have been widely investigated in regenerative medicine because of their immunomodulatory, anti-inflammatory, and reparative properties. Current evidence indicates that many of their effects are mediated by paracrine and intercellular mechanisms rather than sustained engraftment or direct neural replacement. This narrative review synthesizes how MSCs and MSC-derived extracellular vesicles (MSC-EVs) may modulate neuroplasticity in the central nervous system (CNS). MSC-mediated effects include trophic and immunomodulatory signaling, mitochondrial transfer via tunneling nanotubes (TNTs), efferocytosis of apoptotic MSCs by host phagocytes, blood-brain barrier stabilization, and secondary modulation of glymphatic and interstitial fluid clearance. MSC-EVs additionally deliver proteins, lipids, microRNAs, and long non-coding RNAs that regulate inflammatory and reparative gene-expression programs through well-supported post-transcriptional and emerging epigenetic mechanisms. These processes may promote neurite remodeling, angiogenesis, mitochondrial recovery, and attenuation of neuroinflammation, and may support the clearance of neurotoxic proteins. The evidence is organized into five CNS disorder macrocategories defined by shared pathophysiological processes and overlapping therapeutic targets: cerebrovascular and ischemic/hemorrhagic disorders; neurodegenerative proteinopathies and related disorders; neurotrauma and acute lesions; autoimmune, inflammatory, and emerging disorders; and retinal diseases as CNS-related sensory disorders. Although substantial preclinical evidence and encouraging early clinical signals support continued investigation, adequately powered confirmatory trials are still needed to establish whether MSC-based thera5pies can produce durable disease-modifying effects in neurodegenerative disorders. Translation is further limited by variability in cell sources, manufacturing procedures, doses, delivery routes, potency assays, and patient stratification by disease stage and biological phenotype. A cohesive translational roadmap should therefore combine Good Manufacturing Practice (GMP)-compliant production and mechanism-relevant potency testing with the 2025 International Society for Cell & Gene Therapy (ISCT) reporting framework. Finally, engineered MSC-EVs with modified surfaces or defined cargo may enable more targeted and controllable cell-free strategies for CNS repair. See also the graphical abstract(Fig. 1).