Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells

• Published in: PloS one Vol. 10; no. 2; p. e0118020
• Main Authors: Wheeler, Heather E, Wing, Claudia, Delaney, Shannon M, Komatsu, Masaaki, Dolan, M Eileen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.02.2015; Public Library of Science (PLoS)
• Subjects: Antineoplastic Agents - toxicity; Apoptosis; Axonogenesis; Cancer therapies; Cell Line; Chemotherapy; Cisplatin; Clinical trials; Drug dosages; Drug screening; Drugs; Experiments; Gene expression; Gene Expression Regulation - drug effects; Gene Silencing; Genetic diversity; Genetic variance; Genomes; Hematology; Humans; Induced Pluripotent Stem Cells - cytology; Inhibitory postsynaptic potentials; Medical research; Medicine; Neural stem cells; Neurites - drug effects; Neurites - metabolism; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; Oncology; Paclitaxel; Paclitaxel - toxicity; Pain; Patients; Peripheral neuropathy; Perturbation methods; Phenotype; Pluripotency; RNA, Small Interfering - genetics; Stem cells; Toxicity; Tubulin - deficiency; Tubulin - genetics; Vincristine; United States > US; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0118020

There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN), the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs) as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05). The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 ± 0.06 decrease in total neurite outgrowth, P = 0.011). The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05), demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN.