The Reparative Mechanisms Underlying Preclinical Neural Stem/Progenitor Cell Therapy for Ischemic Stroke: A Systematic Review.

Background: Ischemic stroke is a major cause of death and disability worldwide. Current treatments, such as thrombolysis and mechanical thrombectomy, restore perfusion but do not promote tissue repair, highlighting the need for regenerative therapies. Neural stem/progenitor cells (NSPCs) have been extensively explored in preclinical models; however, the mechanisms underlying their therapeutic effects remain incompletely defined. Methods: This study followed the PRISMA guidelines to address the cellular and molecular mechanisms that underlie the neurorestorative effects of transplanted NSPCs in animal models of ischemic stroke. Preclinical studies published between 2013 and 2023 were identified through PubMed, Scopus, and Google Scholar. Eligible studies compared NSPC monotherapy with vehicle-treated controls, and data on transplantation protocols and functional, histological, and biochemical outcomes were extracted for narrative synthesis. Of the 8697 records identified, 25 met the inclusion criteria, with moderate methodological quality (median CAMARADES score: 6/10; range: 3-8). Results: NSPC transplantation significantly improved motor, sensory, and cognitive function while reducing infarct volume, neuronal apoptosis, neuroinflammation, and blood-brain barrier disruption, alongside increased neurotrophic and angiogenic factors (BDNF, GDNF, VEGF, and Ang-1) and modulation of inflammatory mediators. Functional recovery was more consistently associated with paracrine and immunomodulatory mechanisms than with direct neuronal replacement, which occurred less frequently and was often accompanied by astrocytic or oligodendroglial differentiation; astrocytic responses were conflicting, suggesting context-dependent effects. These preclinical mechanisms have not been consistently replicated in early-phase human trials, pointing to immunogenicity and delivery route as key translational barriers. Conclusion: The reparative benefits of NSPC therapy in ischemic stroke are largely attributable to paracrine and immunomodulatory mechanisms, with neuronal replacement playing a minor role. Future studies should focus on strategies to potentiate paracrine activity, improve graft survival, and adopt translationally relevant, comorbidity-inclusive models to advance clinical translation.