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 Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system

2014 ◽  
Vol 6 (255) ◽  
pp. 255ra130-255ra130 ◽  
Author(s):  
Antje D. Ebert ◽  
Kazuki Kodo ◽  
Ping Liang ◽  
Haodi Wu ◽  
Bruno C. Huber ◽  
...  
Keyword(s):  
Stem Cell ◽  
Genetic Polymorphism ◽  
Cell Survival ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Induced Pluripotent Stem Cell ◽  
Model System ◽  
Ischemic Damage ◽  
Aldehyde Dehydrogenase 2 ◽  
Induced Pluripotent

Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation gave rise to elevated amounts of reactive oxygen species and toxic aldehydes, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. We established that ALDH2 controls cell survival decisions by modulating oxidative stress levels and that this regulatory circuitry was dysfunctional in the loss-of-function ALDH2*2 genotype, causing up-regulation of apoptosis in cardiomyocytes after ischemic insult. These results reveal a new function for the metabolic enzyme ALDH2 in modulation of cell survival decisions. Insight into the molecular mechanisms that mediate ALDH2*2-related increased ischemic damage is important for the development of specific diagnostic methods and improved risk management of CAD and may lead to patient-specific cardiac therapies.

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 The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

2020 ◽  
Vol 21 (2) ◽  
pp. 657 ◽  
Author(s):  
Marc Pourrier ◽  
David Fedida
Keyword(s):  
Stem Cell ◽  
Ion Channel ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Induced Pluripotent Stem Cell ◽  
Transgenic Animal ◽  
Cardiac Diseases ◽  
Disease Phenotype ◽  
Induced Pluripotent

There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.

scholarly journals Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Afford New Opportunities in Inherited Cardiovascular Disease Modeling

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Daniel R. Bayzigitov ◽  
Sergey P. Medvedev ◽  
Elena V. Dementyeva ◽  
Sevda A. Bayramova ◽  
Evgeny A. Pokushalov ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Laboratory Animals ◽  
Patient Specific ◽  
Induced Pluripotent

Fundamental studies of molecular and cellular mechanisms of cardiovascular disease pathogenesis are required to create more effective and safer methods of their therapy. The studies can be carried out only when model systems that fully recapitulate pathological phenotype seen in patients are used. Application of laboratory animals for cardiovascular disease modeling is limited because of physiological differences with humans. Since discovery of induced pluripotency generating induced pluripotent stem cells has become a breakthrough technology in human disease modeling. In this review, we discuss a progress that has been made in modeling inherited arrhythmias and cardiomyopathies, studying molecular mechanisms of the diseases, and searching for and testing drug compounds using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

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.

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