Comprehensive review of mesenchymal stem cell (MSC) therapy in Parkinson’s disease that synthesizes preclinical mechanisms (immunomodulation, neurotrophic factors, exosomes/proteostasis), early-phase clinical safety/feasibility and symptomatic signals, and key translational challenges (dosing,…

Valuable for therapeutic discovery because it links biologically plausible, inflammation- and proteostasis-targeting mechanisms to early clinical data and clearly identifies manufacturability, potency, and biomarker gaps that must be resolved to enable rigorous disease-modifying MSC trials.

Parkinson's disease (PD) is a gradual neurodegenerative condition characterized by dopaminergic neuron death, α-synuclein pathology, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Current treatments (levodopa, deep brain stimulation (DBS), etc.) are mainly symptomatic and have limited effect on slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are emerging candidates for a disease-modifying approach because they can modulate both the adaptive and innate immune responses, secreting neurotrophic and pro-angiogenic factors, affecting glial phenotype, and delivering extracellular vesicles/exosomes, which may lessen neuroinflammation and/or proteotoxic stress. Early-phase clinical research (phase 1 dose escalation of intravenous (IV) allogeneic bone marrow (BM)-derived MSCs; recent phase 2 randomized placebo-controlled IV allogeneic MSC trials) indicates that MSCs may be feasible and safe in the short term, although these have demonstrated some symptomatic benefits in motor outcomes. However, notable variability exists across dosing regimens, and significant placebo effects were observed. In this review, we summarize the sources of MSCs, relevant mechanisms of MSC activity in PD biology (including preclinical evidence), clinical trial results, safety issues, routes of administration, and challenges (including potency assays, batch variation, endpoint selection, durability, and regulatory/ethical limitations). We conclude that MSC-based interventions in PD remain investigational, and future clinical trials should focus on standardizing manufacturing processes, utilizing robust potency metrics, incorporating biomarker-rich designs, and selecting clinically meaningful endpoints.