Bridging Regenerative and Restorative Stem Cell Therapies in Parkinson's Disease.

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.