Mesenchymal Stem/Stromal Cell Dysfunction as an Early Pathological Feature of Parkinson's Disease: Implications for Allogeneic Cell Therapy

PD is associated with marked heterogeneity in immune signatures, indicating that therapeutic strategies targeting individual immune cell populations are unlikely to be broadly effective and instead reflect a failure of upstream systemic immunoregulation. While bone marrow–derived mesenchymal stem/stromal cells (BMMSCs) are critical regulators of immune homeostasis and regenerative responses, their functional status during PD progression has not been investigated. Using a combination of MPTP-induced rat chronic PD model, patient-derived induced pluripotent stem cell (iPSC), and in vitro and in vivo transplantation paradigms, we examined MSC function across disease stages. We assessed MSC proliferation, survival, migration, differentiation, oxidative stress, and immunomodulatory capacity, and evaluated their impact on neuroinflammation, dopaminergic-neurodegeneration, neurogenesis, and motor-function. We identify early and progressive MSC dysfunction, emerging during the pre-motor stage and preceding motor deficits. In MPTP-treated rats, bone marrow–derived MSC impairment coincided with early dopaminergic-neuron loss, microglial-activation, and elevated TNF-α & NLRP3 levels. Patient-derived sporadic PD-iMSCs recapitulated these defects, exhibiting reduced proliferation and survival, impaired migration, elevated oxidative stress, diminished differentiation potential, and—most critically—profound loss of immunomodulatory capacity. Autologous PD-iMSCs failed to suppress hyperactivated patient immune cells and showed reduced therapeutic efficacy in vivo, whereas healthy donor-derived iMSCs robustly attenuated peripheral and neuroinflammation, enhanced dopaminergic-neurons, promoted substantia-nigra neurogenesis, and improved motor outcomes. These findings indicate that peripheral MSC integrity critically determines CNS inflammatory tone and regenerative capacity, revealing MSC dysfunction as a systemic driver of neurodegeneration rather than a secondary consequence of PD. It also highlights the strong translational rationale for prioritizing allogeneic MSC-based therapeutic strategies in PD.