RT Journal Article
SR Electronic
T1 Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.04.134262
DO 10.1101/2020.06.04.134262
A1 Chenling Xiong
A1 Katherina C. Chua
A1 Tore B. Stage
A1 Jeffrey Kim
A1 Anne Altman-Merino
A1 Daniel Chan
A1 Krishna Saraf
A1 Amanda Canato Ferracini
A1 Faranak Fattahi
A1 Deanna L. Kroetz
YR 2020
UL http://biorxiv.org/content/early/2020/06/05/2020.06.04.134262.abstract
AB 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 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.Competing Interest StatementThe authors have declared no competing interest.