Home > Publications Database > Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC)-derived sensory neurons. > print

001     154864
005     20240208114852.0
024 7 _ |a 10.1016/j.nbd.2021.105391
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024 7 _ |a 0969-9961
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037 _ _ |a DZNE-2021-00442
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Schinke, Christian
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245 _ _ |a Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC)-derived sensory neurons.
260 _ _ |a Orlando, Fla.
|c 2021
|b Academic Press
336 7 _ |a article
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520 _ _ |a Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. We therefore aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as human disease model system for CIPN. Treatment of iPSC-DSN for 24 h with the neurotoxic drugs paclitaxel, bortezomib, vincristine and cisplatin led to axonal blebbing and a dose dependent decline of cell viability in clinically relevant IC50 ranges, which was not observed for the non-neurotoxic compounds doxorubicin and 5-fluorouracil. Paclitaxel treatment effects were less pronounced after 24 h but prominent when treatment was applied for 72 h. Global transcriptome analyses performed at 24 h, i.e. before paclitaxel-induced cell death occurred, revealed the differential expression of genes of neuronal injury, cellular stress response, and sterol pathways. We further evaluated if known neuroprotective strategies can be reproduced in iPSC-DSN and observed protective effects of lithium replicating findings from rodent dorsal root ganglia cells. Comparing sensory neurons derived from two different healthy donors, we found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.
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650 _ 7 |a 3R
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650 _ 7 |a Chemotherapy induced neuropathy
|2 Other
650 _ 7 |a Induced pluripotent stem cell derived sensory neurons (iPSC-DSN)
|2 Other
650 _ 7 |a Lithium
|2 Other
650 _ 7 |a Replacement
|2 Other
650 _ 7 |a Transcriptome
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650 _ 2 |a Antineoplastic Agents: toxicity
|2 MeSH
650 _ 2 |a Axons: drug effects
|2 MeSH
650 _ 2 |a Axons: pathology
|2 MeSH
650 _ 2 |a Cell Line
|2 MeSH
650 _ 2 |a Cell Survival: drug effects
|2 MeSH
650 _ 2 |a Cell Survival: physiology
|2 MeSH
650 _ 2 |a Dose-Response Relationship, Drug
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: drug effects
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: pathology
|2 MeSH
650 _ 2 |a Sensory Receptor Cells: drug effects
|2 MeSH
650 _ 2 |a Sensory Receptor Cells: pathology
|2 MeSH
650 _ 2 |a Time-Lapse Imaging: methods
|2 MeSH
700 1 _ |a Fernandez Vallone, Valeria
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700 1 _ |a Ivanov, Andranik
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700 1 _ |a Peng, Yangfan
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700 1 _ |a Körtvelyessy, Péter
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700 1 _ |a Nolte, Luca
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700 1 _ |a Huehnchen, Petra
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700 1 _ |a Beule, Dieter
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700 1 _ |a Stachelscheid, Harald
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700 1 _ |a Boehmerle, Wolfgang
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700 1 _ |a Endres, Matthias
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|e Last author
773 _ _ |a 10.1016/j.nbd.2021.105391
|g Vol. 155, p. 105391 -
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|t Neurobiology of disease
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