(F1291) EARLY AND PROGRESSIVE DYSFUNCTION OF ENDOGENOUS BONE MARROW MESENCHYMAL STROMAL CELLS IN PARKINSON’S DISEASE: IMPLICATIONS FOR REGENERATIVE THERAPY
PhD Scholar National Institute of Mental Health and Neurosciences Bengaluru, India
Abstract: Chronic and self-sustaining cycles of peripheral and neuroinflammation are now recognized as key drivers of dopaminergic (DA) neuron degeneration and the progression of Parkinson’s disease (PD). Intriguingly, preclinical and clinical studies have consistently shown a strong association between prior exposure to chronic inflammatory conditions and an increased risk of developing PD. Systemic immune imbalances are typically regulated by immunomodulatory cells such as bone marrow-derived mesenchymal stromal cells (MSCs). While autologous MSC transplantation in PD patients has demonstrated transient motor improvements, its lack of sustained benefits underscores the need to study endogenous MSCs under disease conditions before they can be considered viable therapeutic candidates. In a chronic in vivo PD model induced by MPTP, we examined the status of endogenous MSCs during both premotor and motor stages. Our results indicate that MSC dysfunction begins early, at the premotor stage, and progressively worsens with disease advancement. Transplantation of healthy rat MSCs at the premotor stage effectively halted neurodegeneration, promoted neurogenesis, and mitigated inflammation. Additionally, we assessed the similar physiological and functional parameters in sporadic PD patient iPSC-derived MSCs (PD-iMSCs) which showed impaired proliferation, differentiation, migration, and immunomodulatory functions, alongside elevated basal ROS levels. When transplanted into MPTP rats, PD-iMSCs failed to curb inflammation, prevent neurodegeneration, or restore motor function, unlike healthy iPSC-derived MSCs, which were effective when administered early. This study is the first to demonstrate that endogenous MSC dysfunction in PD correlates with midbrain gliosis and inflammation, emphasizing the importance of early intervention to preserve MSC function and develop effective regenerative therapies.
Funding Source: Indian Council of Medical Research (ICMR), Department of Science and Technology (DST), India Department of Biotechnology (DBT), India
