Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
Chemotherapy−induced peripheral neuropathy (CIPN) is a dose−limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell−derived sensory neuron (iPSC−SN) model was developed for the study of chemotherapy−induced neurotoxicity. The iPSC−SNs express proteins
... teins characteristic of nociceptor, mechanoreceptor and proprioceptor sensory neurons and show Ca2+ influx in response to capsaicin, α,β−meATP and glutamate. iPSC−SNs are relatively resistant to the cytotoxic effects of paclitaxel, with IC50 values of 38.1 μM (95% CI: 22.9 − 70.9 μM) for 48 hr exposure and 9.3 μM (95% CI: 5.7 − 16.5 μM) for 72 hr treatment. Paclitaxel causes dose− and time−dependent changes in neurite network complexity detected by βIII−tubulin staining and high content imaging. The IC50 for paclitaxel reduction of neurite area was 1.4 μM (95% CI: 0.3 - 16.9 μM) for 48 hr exposure and 0.6 μM (95% CI: 0.09 - 9.9 μM) for 72 hr exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites and changes in glutamate−induced neuronal excitability were also observed with paclitaxel exposure. The iPSC−SNs were also sensitive to docetaxel, vincristine and bortezomib. Collectively, these data support the use of iPSC−SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.