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Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons.
Schinke, Christian; Fernandez Vallone, Valeria; Ivanov, Andranik; Peng, Yangfan; Körtvelyessy, Péter; Nolte, Luca; Huehnchen, Petra; Beule, Dieter; Stachelscheid, Harald; Boehmerle, Wolfgang; Endres, Matthias.
Afiliación
  • Schinke C; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 1
  • Fernandez Vallone V; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Stem Cell Core Facility, Augustenburger Platz 1, 13353 Berlin, Germany.
  • Ivanov A; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics, Charitéplatz 1, 10117 Berlin, Germany.
  • Peng Y; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Univ
  • Körtvelyessy P; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-U
  • Nolte L; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany.
  • Huehnchen P; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 1
  • Beule D; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics, Charitéplatz 1, 10117 Berlin, Germany; Max-Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
  • Stachelscheid H; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Stem Cell Core Facility, Augustenburger Platz 1, 13353 Berlin, Germany.
  • Boehmerle W; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 1
  • Endres M; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Klinik und Hochschulambulanz für Neurologie, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Anna-Louisa-Karsch Straße 2, 1
Neurobiol Dis ; 155: 105391, 2021 07.
Article en En | MEDLINE | ID: mdl-33984509
ABSTRACT
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Receptoras Sensoriales / Axones / Supervivencia Celular / Células Madre Pluripotentes Inducidas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Receptoras Sensoriales / Axones / Supervivencia Celular / Células Madre Pluripotentes Inducidas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Neurobiol Dis Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article