TY  - JOUR
AU  - Schinke, Christian
AU  - Fernandez Vallone, Valeria
AU  - Ivanov, Andranik
AU  - Peng, Yangfan
AU  - Körtvelyessy, Péter
AU  - Nolte, Luca
AU  - Huehnchen, Petra
AU  - Beule, Dieter
AU  - Stachelscheid, Harald
AU  - Boehmerle, Wolfgang
AU  - Endres, Matthias
TI  - Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC)-derived sensory neurons.
JO  - Neurobiology of disease
VL  - 155
SN  - 0969-9961
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2021-00442
SP  - 105391
PY  - 2021
AB  - 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.
KW  - Antineoplastic Agents: toxicity
KW  - Axons: drug effects
KW  - Axons: pathology
KW  - Cell Line
KW  - Cell Survival: drug effects
KW  - Cell Survival: physiology
KW  - Dose-Response Relationship, Drug
KW  - Humans
KW  - Induced Pluripotent Stem Cells: drug effects
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Sensory Receptor Cells: drug effects
KW  - Sensory Receptor Cells: pathology
KW  - Time-Lapse Imaging: methods
KW  - 3R (Other)
KW  - Chemotherapy induced neuropathy (Other)
KW  - Induced pluripotent stem cell derived sensory neurons (iPSC-DSN) (Other)
KW  - Lithium (Other)
KW  - Replacement (Other)
KW  - Transcriptome (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33984509
DO  - DOI:10.1016/j.nbd.2021.105391
UR  - https://pub.dzne.de/record/154864
ER  -