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000154864 037__ $$aDZNE-2021-00442
000154864 041__ $$aEnglish
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000154864 1001_ $$0P:(DE-HGF)0$$aSchinke, Christian$$b0
000154864 245__ $$aModeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC)-derived sensory neurons.
000154864 260__ $$aOrlando, Fla.$$bAcademic Press$$c2021
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000154864 520__ $$aChemotherapy-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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000154864 650_7 $$2Other$$a3R
000154864 650_7 $$2Other$$aChemotherapy induced neuropathy
000154864 650_7 $$2Other$$aInduced pluripotent stem cell derived sensory neurons (iPSC-DSN)
000154864 650_7 $$2Other$$aLithium
000154864 650_7 $$2Other$$aReplacement
000154864 650_7 $$2Other$$aTranscriptome
000154864 650_2 $$2MeSH$$aAntineoplastic Agents: toxicity
000154864 650_2 $$2MeSH$$aAxons: drug effects
000154864 650_2 $$2MeSH$$aAxons: pathology
000154864 650_2 $$2MeSH$$aCell Line
000154864 650_2 $$2MeSH$$aCell Survival: drug effects
000154864 650_2 $$2MeSH$$aCell Survival: physiology
000154864 650_2 $$2MeSH$$aDose-Response Relationship, Drug
000154864 650_2 $$2MeSH$$aHumans
000154864 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: drug effects
000154864 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: pathology
000154864 650_2 $$2MeSH$$aSensory Receptor Cells: drug effects
000154864 650_2 $$2MeSH$$aSensory Receptor Cells: pathology
000154864 650_2 $$2MeSH$$aTime-Lapse Imaging: methods
000154864 7001_ $$0P:(DE-HGF)0$$aFernandez Vallone, Valeria$$b1
000154864 7001_ $$0P:(DE-HGF)0$$aIvanov, Andranik$$b2
000154864 7001_ $$0P:(DE-HGF)0$$aPeng, Yangfan$$b3
000154864 7001_ $$0P:(DE-2719)2812030$$aKörtvelyessy, Péter$$b4
000154864 7001_ $$0P:(DE-HGF)0$$aNolte, Luca$$b5
000154864 7001_ $$0P:(DE-HGF)0$$aHuehnchen, Petra$$b6
000154864 7001_ $$0P:(DE-HGF)0$$aBeule, Dieter$$b7
000154864 7001_ $$0P:(DE-HGF)0$$aStachelscheid, Harald$$b8
000154864 7001_ $$0P:(DE-HGF)0$$aBoehmerle, Wolfgang$$b9
000154864 7001_ $$0P:(DE-2719)2811033$$aEndres, Matthias$$b10$$eLast author
000154864 773__ $$0PERI:(DE-600)1471408-5$$a10.1016/j.nbd.2021.105391$$gVol. 155, p. 105391 -$$p105391$$tNeurobiology of disease$$v155$$x0969-9961$$y2021
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