Modeling Transposition of the Great Arteries with Patient-Specific Induced Pluripotent Stem Cells

Ontoria‐Oviedo, Imelda; Földes, Gábor; Tejedor, Sandra; Panadero, Joaquín; Kitani, Tomoya; Vázquez, A; Wu, Joseph C.; Harding, Siân E.; Sepúlveda, Pilar

doi:10.3390/ijms222413270

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…Ethical approval for using the hiPSCs was provided via 108-88-1 within the project SAF2009-07965 funded by the “Ministerio economía y competitividad,” Spain. This line was generated from foreskin fibroblasts using a lentiviral vector expressing the OCT4 , NANOG , LIN28 , and SOX2 genes ( 49 ). Different clones were obtained and validated using the following assays: alkaline phosphatase, surface marker expression, pluripotency gene expression, transgene silencing, proviral integration, and in vitro differentiation.…”

Section: Methodsmentioning

confidence: 99%

WiChR, a highly potassium-selective channelrhodopsin for low-light one- and two-photon inhibition of excitable cells

et al. 2022

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The electric excitability of muscle, heart, and brain tissue relies on the precise interplay of Na + - and K + -selective ion channels. The involved ion fluxes are controlled in optogenetic studies using light-gated channelrhodopsins (ChRs). While non-selective cation-conducting ChRs are well established for excitation, K + -selective ChRs (KCRs) for efficient inhibition have only recently come into reach. Here, we report the molecular analysis of recently discovered KCRs from the stramenopile Hyphochytrium catenoides and identification of a novel type of hydrophobic K + selectivity filter. Next, we demonstrate that the KCR signature motif is conserved in related stramenopile ChRs. Among them, WiChR from Wobblia lunata features a so far unmatched preference for K + over Na + , stable photocurrents under continuous illumination, and a prolonged open-state lifetime. Showing high expression levels in cardiac myocytes and neurons, WiChR allows single- and two-photon inhibition at low irradiance and reduced tissue heating. Therefore, we recommend WiChR as the long-awaited efficient and versatile optogenetic inhibitor.

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Section: Methodsmentioning

confidence: 99%

WiChR, a highly potassium-selective channelrhodopsin for low-light one- and two-photon inhibition of excitable cells

et al. 2022

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“…The use of induced pluripotent stem cells (iPSCs) offers a powerful model for studying disease mechanisms associated with specific cell types [20,21], allowing for the identification of key molecular circuits and potential therapeutic targets [22]. In this context, investigating the mechanisms of anthracycline-induced cardiotoxicity can be accomplished using human iPSC-derived ventricular cardiomyocytes (hiPSC-CMs) of patients who develop cardiotoxicity after antineoplastic treatment.…”

Section: Introductionmentioning

confidence: 99%

Modeling Cardiotoxicity in Pediatric Oncology Patients Using Patient-Specific iPSC-Derived Cardiomyocytes Reveals Downregulation of Cardioprotective microRNAs

et al. 2023

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Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

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Translational potential of hiPSCs in predictive modeling of heart development and disease

Mansfield

Zhao

Basu

2022

Birth Defects Research

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Congenital heart disease (CHD) represents a major class of birth defects worldwide and is associated with cardiac malformations that often require surgical intervention immediately after birth. Despite the intense efforts from multicentric genome/exome sequencing studies that have identified several genetic variants, the etiology of CHD remains diverse and often unknown. Genetically modified animal models with candidate gene deficiencies continue to provide novel molecular insights that are responsible for fetal cardiac development. However, the past decade has seen remarkable advances in the field of human induced pluripotent stem cell (hiPSC)‐based disease modeling approaches to better understand the development of CHD and discover novel preventative therapies. The iPSCs are derived from reprogramming of differentiated somatic cells to an embryonic‐like pluripotent state via overexpression of key transcription factors. In this review, we describe how differentiation of hiPSCs to specialized cardiac cellular identities facilitates our understanding of the development and pathogenesis of CHD subtypes. We summarize the molecular and functional characterization of hiPSC‐derived differentiated cells in support of normal cardiogenesis, those that go awry in CHD and other heart diseases. We illustrate how stem cell‐based disease modeling enables scientists to dissect the molecular mechanisms of cell–cell interactions underlying CHD. We highlight the current state of hiPSC‐based studies that are in the verge of translating into clinical trials. We also address limitations including hiPSC‐model reproducibility and scalability and differentiation methods leading to cellular heterogeneity. Last, we provide future perspective on exploiting the potential of hiPSC technology as a predictive model for patient‐specific CHD, screening pharmaceuticals, and provide a source for cell‐based personalized medicine. In combination with existing clinical and animal model studies, data obtained from hiPSCs will yield further understanding of oligogenic, gene–environment interaction, pathophysiology, and management for CHD and other genetic cardiac disorders.

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Modeling Transposition of the Great Arteries with Patient-Specific Induced Pluripotent Stem Cells

Cited by 4 publications

References 41 publications

WiChR, a highly potassium-selective channelrhodopsin for low-light one- and two-photon inhibition of excitable cells

WiChR, a highly potassium-selective channelrhodopsin for low-light one- and two-photon inhibition of excitable cells

Modeling Cardiotoxicity in Pediatric Oncology Patients Using Patient-Specific iPSC-Derived Cardiomyocytes Reveals Downregulation of Cardioprotective microRNAs

Translational potential of hiPSCs in predictive modeling of heart development and disease

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