Cell Therapy Targeting Pathological Networks in Neurodegenerative Diseases: Mechanisms and Translation from Stem Cells to Extracellular Vesicles.

Abstract

Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are characterized by interacting pathological processes such as protein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. This narrative review examines how embryonic/ induced pluripotent stem cells, neural stem cells, mesenchymal stem/stromal cells, immune cells, and extracellular vesicles may intervene across these pathological networks. A targeted PubMed search and reference-list screening through 5 July 2026 identified relevant mechanistic, preclinical, clinical, manufacturing, and regulatory evidence. The reviewed strategies act through cell replacement, paracrine support, immunomodulation, metabolic stabilization, and pathological- protein clearance. Evidence maturity differs substantially by disease and product: pluripotent stem cell-derived dopaminergic progenitors have entered early clinical evaluation in Parkinson's disease, whereas most mesenchymal stem/stromal cell studies remain small and exploratory, and immune-cell and extracellular-vesicle approaches are predominantly preclinical or early translational. Major barriers include product heterogeneity, mechanism-linked potency testing, longterm safety, delivery and dose optimization, disease-stage selection, clinically meaningful endpoints, and regulatory comparability. Future development should emphasize standardized manufacturing, biomarker-guided trial design, transparent reporting of negative findings, and rational combinations with pharmacological or gene-based therapies. Cell-based interventions remain promising, but durable clinical benefit has not yet been established.