scholarly journals Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

2020 ◽  
Author(s):  
Chenling Xiong ◽  
Katherina C. Chua ◽  
Tore B. Stage ◽  
Josefina Priotti ◽  
Jeffrey Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Neurotoxic Effects ◽  
Induced Pluripotent

scholarly journals Dataset for: Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC)-derived sensory neurons

Data in Brief ◽  
2021 ◽  
Vol 38 ◽  
pp. 107320
Author(s):  
Christian Schinke ◽  
Valeria Fernandez Vallone ◽  
Andranik Ivanov ◽  
Yangfan Peng ◽  
Péter Körtvelyessy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

2020 ◽  
Author(s):  
Chenling Xiong ◽  
Katherina C. Chua ◽  
Tore B. Stage ◽  
Jeffrey Kim ◽  
Anne Altman-Merino ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Induced Pluripotent Stem Cell ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Effects ◽  
Prevention And Treatment ◽  
Induced Pluripotent

AbstractChemotherapy-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.

scholarly journals Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

2018 ◽  
Author(s):  
Jiun-I Lai ◽  
Daniel Nachun ◽  
Lina Petrosyan ◽  
Benjamin Throesch ◽  
Erica Campau ◽  
...  
Keyword(s):  
Nervous System ◽  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Neuronal Cells ◽  
Friedreich Ataxia ◽  
Induced Pluripotent Stem Cell ◽  
Repeat Expansion ◽  
Mrna Levels ◽  
Induced Pluripotent

AbstractFriedreich ataxia (FRDA) is a rare childhood neurodegenerative disorder with no effective treatment. FRDA is caused by transcriptional silencing of the FXN gene and consequent loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA•TTC repeat expansion in the first intron of FXN leads to heterochromatin formation and gene silencing, we have shown that members of the 2-aminobenzamide family of histone deacetylase inhibitors (HDACi) reproducibly increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neuronal cells and in peripheral blood mononuclear cells from patients treated with the drug in a phase I clinical trial. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similarly to other triplet repeat disorders, it is not known why only specific cells types are affected in the disease, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome editing techniques offers the unique possibility of addressing these questions in a relevant cell model of the disease, without the confounding effect of different genetic backgrounds. We derived a set of isogenic iPSC lines that differ only in the length of the GAA•TTC repeats, using “scarless” gene-editing methods (helper-dependent adenovirus-mediated homologous recombination). To uncover the gene expression signature due to GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons by RNA sequencing. We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

scholarly journals KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Jun-Hui Yuan ◽  
Mark Estacion ◽  
Malgorzata A Mis ◽  
Brian S Tanaka ◽  
Betsy R Schulman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Missense Variant ◽  
Pain Modulation ◽  
Dorsal Root Ganglion Neurons ◽  
Patient Specific ◽  
Induced Pluripotent ◽  
Ganglion Neurons

Abstract There is a pressing need for understanding of factors that confer resilience to pain. Gain-of-function mutations in sodium channel Nav1.7 produce hyperexcitability of dorsal root ganglion neurons underlying inherited erythromelalgia, a human genetic model of neuropathic pain. While most individuals with erythromelalgia experience excruciating pain, occasional outliers report more moderate pain. These differences in pain profiles in blood-related erythromelalgia subjects carrying the same pain-causative Nav1.7 mutation and markedly different pain experience provide a unique opportunity to investigate potential genetic factors that contribute to inter-individual variability in pain. We studied a patient with inherited erythromelalgia and a Nav1.7 mutation (c.4345T>G, p. F1449V) with severe pain as is characteristic of most inherited erythromelalgia patients, and her mother who carries the same Nav1.7 mutation with a milder pain phenotype. Detailed six-week daily pain diaries of pain episodes confirmed their distinct pain profiles. Electrophysiological studies on subject-specific induced pluripotent stem cell-derived sensory neurons from each of these patients showed that the excitability of these cells paralleled their pain phenotype. Whole-exome sequencing identified a missense variant (c.2263C>T, p. D755N) in KCNQ3 (Kv7.3) in the pain resilient mother. Voltage-clamp recordings showed that co-expression of Kv7.2-wild type (WT)/Kv7.3-D755N channels produced larger M-currents than that of Kv7.2-WT/Kv7.3-WT. The difference in excitability of the patient-specific induced pluripotent stem cell-derived sensory neurons was mimicked by modulating M-current levels using the dynamic clamp and a model of the mutant Kv7.2-WT/Kv7.3-D755N channels. These results show that a ‘pain-in-a-dish’ model can be used to explicate genetic contributors to pain, and confirm that KCNQ variants can confer pain resilience via an effect on peripheral sensory neurons.

scholarly journals Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons

2021 ◽  
pp. 105391
Author(s):  
Christian Schinke ◽  
Valeria Fernandez Vallone ◽  
Andranik Ivanov ◽  
Yangfan Peng ◽  
Péter Körtvelyessy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sensory Neurons ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

Use of 3D culture systems to generate human induced pluripotent stem cell-derived [beta]-cells in vitro

2018 ◽  
Author(s):  
Fantuzzi Federica ◽  
Toivonen Sanna ◽  
Schiavo Andrea Alex ◽  
Pachera Nathalie ◽  
Rajaei Bahareh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Beta Cells ◽  
Pluripotent Stem Cell ◽  
3D Culture ◽  
Induced Pluripotent Stem Cell ◽  
Culture Systems ◽  
Induced Pluripotent
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