Pre-motor Mesenchymal stromal Cell Dysfunction Drives Immune Dysregulation in Parkinson’s Disease

Parkinson's disease (PD) is characterized by chronic neuroinflammation and peripheral immune dysfunction, yet the mechanisms underlying systemic-immunomodulatory failure remain unclear. Here we demonstrate that mesenchymal stromal cell (MSC) dysfunction represents an early pathological feature of PD, occurring during the pre-motor phase. Using MPTP-induced rat model, we show that bone-marrow MSC impairment emerges at week 1 post-treatment, coinciding with dopaminergic neurodegeneration but preceding motor-symptoms, with reduced proliferation, impaired migration, elevated oxidative stress, and diminished immunomodulatory capacity. Patient-derived induced pluripotent stem cell-derived MSCs (iMSCs) from sporadic-PD patients recapitulated these dysfunctions and exhibited severely compromised ability to suppress peripheral-blood mononuclear-cell proliferation and PD patient PBMCs in immunomodulation assays. Transplantation studies in MPTP-induced rats revealed that healthy-control iMSCs provided superior neuroprotection, reduced inflammation, promoted neurogenesis, and improved motor-function versus PD-iMSCs. These findings identify MSC immunomodulatory-dysfunction as an upstream contributor to PD pathogenesis and provide rationale for allogeneic over autologous MSC therapeutic strategies in PD treatment.