(W1080) Reactive oxygen species from mitochondria drive excessive differentiation of neural stem/progenitor cells following non-cytotoxic exposure to cisplatin
Academic Postdoctoral Fellow Universidad de los Andes, Region Metropolitana, Chile
Abstract: Neural stem and progenitor cells (NSPCs) are essential for nervous system development, as they self-renew and differentiate into neurons and glia. These processes are highly sensitive to environmental and chemical factors, including chemotherapeutic agents like cisplatin, an FDA-approved drug that disrupts DNA replication. While cisplatin effectively targets cancer cells, it also induces side effects, such as nephrotoxicity, ototoxicity, and neurotoxicity. Although its cytotoxic effects are well-documented, less is known about its impact at non-cytotoxic levels. This study examined the effects of non-cytotoxic cisplatin (5 μM) on NSPC differentiation and mitochondrial activity, focusing on reactive oxygen species (ROS) as mediators. Mitochondrial function was analyzed via MTT assays, ATP measurements, and flow cytometry for mitochondrial potential (ΔΨm), biomass, and ROS levels. NSPC self-renewal and differentiation were assessed using microscopy and pharmacological ROS inhibition with Mito-TEMPO. After 24 hours of exposure, cisplatin enhanced mitochondrial activity, evidenced by increased ATP production, ΔΨm, and ROS generation, accompanied by reduced cell cycle progression and self-renewal. This led to exaggerated differentiation into neuronal and glial lineages. ROS inhibition reduced differentiation but failed to restore cell cycle progression and self-renewal. These findings suggest that subtherapeutic cisplatin disrupts NSPC integrity by promoting differentiation through a ROS-dependent mechanism, highlighting the vulnerability of NSPCs even at non-cytotoxic doses. Co-administration of antioxidants during chemotherapy may protect NSPCs and prevent long-term developmental and cognitive risks in vulnerable populations, such as neonates exposed to cisplatin indirectly (e.g., via breastfeeding). Safeguarding the neural stem cell niche is critical to mitigating these risks.
