Photobiomodulation therapy preconditioning modifies nitric oxide pathway and oxidative stress in human-induced pluripotent stem cell-derived ventricular cardiomyocytes treated with doxorubicin

2021 ◽  
Author(s):  
Allan Luís Barboza Atum ◽  
José Almir Alves da Silva ◽  
Danila Marques ◽  
Renato Araújo Prates ◽  
Fernanda Marciano Consolim-Colombo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Photobiomodulation Therapy ◽  
Ventricular Cardiomyocytes ◽  
Induced Pluripotent ◽  
And Oxidative Stress ◽  
Nitric Oxide Pathway

Assessment of Drug Proarrhythmic Potential in Electrically Paced Human Induced Pluripotent Stem Cell–Derived Ventricular Cardiomyocytes Using Multielectrode Array

2020 ◽  
pp. 247255522095320
Author(s):  
Shuyun Bai ◽  
Junjie Pei ◽  
Kan Chen ◽  
Ya Zhao ◽  
Henghua Cao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Field Potential ◽  
Induced Pluripotent Stem Cell ◽  
Multielectrode Array ◽  
Drug Induced ◽  
Ventricular Cardiomyocytes ◽  
Wide Range ◽  
Beating Rate ◽  
Induced Pluripotent

Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) have been widely used for the assessment of drug proarrhythmic potential through multielectrode array (MEA). HiPSC-CM cultures beat spontaneously with a wide range of frequencies, however, which could affect drug-induced changes in repolarization. Pacing hiPSC-CMs at a physiological heart rate more closely resembles the state of in vivo ventricular myocytes and permits the standardization of test conditions to improve consistency. In this study, we systematically investigated the time window of stable ion currents in high-purity hiPSC-derived ventricular cardiomyocytes (hiPSC-vCMs) and confirmed that these cells could be used to correctly predict the proarrhythmic risk of Comprehensive In Vitro Proarrhythmia Assay (CiPA) reference compounds. To evaluate drug proarrhythmic potentials at a physiological beating rate, we used a MEA to electrically pace hiPSC-vCMs, and we recorded regular field potential waveforms in hiPSC-vCMs treated with DMSO and 10 CiPA reference drugs. Prolongation of field potential duration was detected in cells after exposure to high- and intermediate-risk drugs; in addition, drug-induced arrhythmia-like events were observed. The results of this study provide a simple and feasible method to investigate drug proarrhythmic potentials in hiPSC-CMs at a physiological beating rate.

Abstract 16472: Deciphering a Mechanistic Link Between Enhanced Late Sodium Current and Triggered Atrial Fibrillation Using Patient-specific and Gene-corrected Induced Pluripotent Stem Cell-derived Atrial Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Liang HONG ◽  
Olivia T Ly ◽  
Hanna Chen ◽  
Arvind Sridhar ◽  
Meihong Zhang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Atrial Fibrillation ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Sodium Current ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Gain Of Function ◽  
Late Sodium Current ◽  
Induced Pluripotent

Introduction: Gain-of-function mutations in SCN5A, which encodes the cardiac sodium channel, have been linked with familial atrial fibrillation (AF). However, the mechanistic link between the late sodium current (I Na,L ) and triggered arrhythmia remains unclear. Hypothesis: To characterize the electrophysiological (EP) phenotype of gain-of-function AF-linked SCN5A mutations, elucidate the underlying cellular mechanisms using patient-specific and gene-corrected (GC) induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs). Methods: We generated iPSC-aCMs from two families carrying SCN5A mutations (E428K and N470K) and control subjects. Whole-cell patch clamp and multi-electrode arrays were recorded to assess the EP phenotypes of the atrial iPSC-CMs. We corrected the E428K iPSC-aCMs using CRISPR/Cas9 gene editing approach (isogenic control). Results: The SCN5A mutation lines displayed abnormal EP properties including increased beating frequency and irregularity with triggered beats characteristic of AF ( Fig. 1 ). E428K iPSC-aCMs displayed spontaneous arrhythmogenic activity with beat-to-beat irregularity ( Fig. 1 A-D ) with the prolonged APD ( Fig. 1 E-H ) associated with enhanced I Na,L ( Fig. 1 I-L ). In contrast, expression of SCN5A -E428K in heterologous expression system failed to show enhanced I Na,L . The gene-corrected E428K iPSC-aCMs normalized the aberrant EP phenotype. Gene expression profiling revealed differential expression of calcium and potassium channel homeostasis and nitric oxide mediated signal transduction which could result in EP remodeling of atrial CMs. Conclusions: Patient-specific and gene-corrected iPSC-aCMs exhibited striking ex-vivo EP phenotype of an AF-causing SCN5A gain-of-function mutation that produced minimal changes in-vitro . We established a mechanistic link between enhanced I Na,L , ion channel remodeling and nitric oxide signaling pathways, and triggered AF.

Abstract 499: Modeling Carfilzomib Induced Cardiotoxicity Using Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Parvin Forghani ◽  
Aysha Rashid ◽  
Dong Li ◽  
Anant Mandawat ◽  
Chunhui XU
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Cell Viability ◽  
Pluripotent Stem Cell ◽  
Motion Vector ◽  
Induced Pluripotent Stem Cell ◽  
Control Group ◽  
Preclinical Research ◽  
Induced Pluripotent

Cardiovascular toxicity post Carfilzomib (Cfz/Kyprolis) therapy has been identified in several clinical settings. A prevalent challenge in side effects of anti-cancer drugs is the translation of findings from preclinical research into clinical practice. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are being used as a physiological in vitro model to overcome some of these challenges. Here we used both 2D and 3D hiPSC-CMs to elucidate the underlying mechanism of post-Cfz cardiotoxicity. hiPSC-CMs were exposed to clinically relevant doses of Cfz based on C max for Cfz (5.88 μM). Data normalization against the control group demonstrates significant reduction in cell viability following two days of treatment with Cfz in 3 different cell lines (IMR-90, SCVI273 and 902). Increased Caspase3/7 activity post Cfz treatment paralleled with a substantial decrease in mitochondrial membrane potential and increase in oxidative stress following Cfz treatment. Also, significant decrease in oxygen consumption rate was observed after one-day exposure. In addition, we observed impaired Ca 2+ handling at the single cell level following Cfz treatment. Using video microscopy with motion vector analysis we also observed significant decrease in contractility of 3D hiPSC-CMs following Cfz treatment. Additionally, we observed disrupted expression of α-actinin, alterations in structural organization of sarcomeres, circularity and aspect ratio. Altogether, these results suggest that Cfz induced cardiotoxicity as indicated by cell viability, oxidative stress, mitochondrial and structural damages along with abnormal Ca 2+ handing and contractility dysfunction.

scholarly journals Control of Oxidative Stress and Generation of Induced Pluripotent Stem Cell-like Cells by Jun Dimerization Protein 2

Cancers ◽  
2013 ◽  
Vol 5 (4) ◽  
pp. 959-984 ◽  
Author(s):  
Shyh-Shin Chiou ◽  
Sophie Wang ◽  
Deng-Chyang Wu ◽  
Ying-Chu Lin ◽  
Li-Pin Kao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent
Sign in / Sign up

Export Citation Format

Share Document