Background: Neuroinflammation contributes to Parkinson's disease (PD) progression and motor dysfunction. Allogeneic human mesenchymal stem cells (allo‐hMSCs) may reduce neuroinflammation and improve motor symptoms. Objectives: To evaluate the efficacy of repeated intravenous doses of 10 × 10 ⁶ /kg allo‐hMSCs in improving motor symptoms in patients with PD (PwP). Methods: In this phase 2, randomized, placebo‐controlled trial (November 2020–July 2023), mild‐to‐moderate PwP received either three allo‐hMSC infusions, one placebo followed by two allo‐hMSC infusions, or three placebo infusions at 18‐week intervals. Follow‐up lasted 88 weeks. The primary outcome was a >70% posterior probability (PP) of a difference in the proportion of participants with ≥5‐point improvement in OFF‐medication Movement Disorder Society Sponsored Revision of the Unified Parkinson's Disease Rating Scale‐Part III (MDS‐UPDRS‐III) at week 62. Bayesian analysis was conducted using R v4.2.0. Results: Forty‐five PwP were enrolled. A larger proportion of subjects achieved a ≥5‐point improvement in MDS‐UPDRS‐III in the three‐infusion arm compared with placebo at week 62 (mean difference [MD]: 5.0%, PP = 93.7%), translating to a 16.9‐point improvement in MDS‐UPDRS‐III in the three‐infusion arm compared with a 14.6‐point improvement in the placebo arm. Conversely, fewer subjects in the two‐infusion arm compared with placebo showed ≥5‐point improvement at week 62 (MD: –62.4%, PP ≥ 99.9%), translating to only a 3.9‐point improvement in MDS‐UPDRS‐III in the two‐infusion arm. However, improvement in MDS‐UPDRS‐III was seen across all treatment arms. Adverse events were mild and transient. Conclusions: Three infusions of 10 × 10 ⁶ allo‐hMSCs/kg improved motor function in mild‐to‐moderate PwP, while two infusions showed less improvement than placebo. To address this discrepancy, future studies should conduct functional potency assays to understand batch‐to‐batch variability affecting clinical efficacy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Early differentiation between PD and atypical parkinsonism is challenging. • Variability in diagnosis can weaken statistical power in trials. • Precise diagnostic tools are needed for trial population homogeneity. • This patient initially diagnosed with PD, was diagnosed with MSA via CSF αSyn-SAA. • Adding αSyn-SAA to inclusion criteria could enhance subject selection in trials.

The prevalence of Parkinson’s disease (PD) is projected to rise, stressing the urgency for disease-modifying therapies. Its complex pathophysiology, characterized by α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation, continues to complicate therapeutic development. Mounting evidence implicates neuroinflammation as both a driver and consequence of disease progression. This highlights the need to address both neuronal loss and the established dysfunctional microenvironment. Consequently, stem cell-based treatments have generated interest for their immunomodulatory, neuroprotective, and regenerative potential. However, therapeutic outcomes are strongly influenced by stem cell type and route of administration, which together determine whether effects are predominantly regenerative or restorative. In this review, we introduce a conceptual framework that situates stem cell therapies for PD along a regenerative–restorative continuum. Regenerative therapies include fetal ventral mesencephalic, embryonic, and induced pluripotent stem cells. When delivered intracerebrally, they aim to reconstruct dopaminergic circuitry through differentiation and engraftment. In contrast, restorative approaches include mesenchymal stem cells, which exert paracrine and immunomodulatory effects to promote neuroprotection and functional stabilization of the neuronal environment. Multilineage-differentiating stress-enduring cells and neural stem cells exhibit both regenerative and restorative features, to differing extents. This framework integrates mechanistic and clinical evidence that may help clarify distinctions across stem cell approaches and inform future translational development in PD.