Mitochondria-derived reactive oxygen species induce over-differentiation of neural stem/progenitor cells after non-cytotoxic cisplatin exposure

作者：Felipe A. Bustamante-Barrientos, Eliana Lara-Barba, Yeimi Herrera-Luna, Cynthia García-Guerrero, Eduardo Silva-Pavez, Jonathan Morales-Reyes, María Jesús Araya, Liliana Yantén-Fuentes, Noymar Luque‐Campos, Claudia Altamirano, Ana María Vega-Letter, Patricia Luz‐Crawford · 发表于：Frontiers in Cell and Developmental Biology · 年份：2025 · DOI：10.3389/fcell.2025.1555153 · 被引用次数：10 · 研究领域：Chemotherapy-induced organ toxicity mitigation、Cancer Treatment and Pharmacology、Cancer-related cognitive impairment studies

Background: Neural stem and progenitor cells (NSPCs) are crucial for nervous system development and self-renewal. However, their properties are sensitive to environmental and chemical factors, including chemotherapy agents like cisplatin, an FDA-approved drug used to treat cancer. Cisplatin inhibits DNA replication but can cause side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. While its cytotoxic effects are well understood, the impact of non-cytotoxic cisplatin concentrations on NSPC differentiation remains unclear. Methods: This study examined how non-cytotoxic cisplatin exposure influences NSPC differentiation and mitochondrial activity, specifically through reactive oxygen species (ROS) generation. Mitochondrial activity was analyzed via tetrazolium salt (MTT) assay, ATP biosynthesis, mitochondrial membrane potential (ΔΨm), biomass, and ROS production. Glycolytic activity was assessed by extracellular acidification and lactate production. Self-renewal capacity and differentiation were measured using flow cytometry and confocal microscopy. Mitochondrial ROS generation was modulated with Mito-TEMPO. Results: After 24 h of non-cytotoxic cisplatin exposure (5 μM), mitochondrial activity increased, as shown by higher MTT conversion, ATP content, ΔΨm, biomass, and ROS levels. Despite a stabilization of mitochondrial activity and ROS production by 72 h, this exposure impaired cell cycle progression, self-renewal, and enhanced differentiation toward neuronal a...