RESUMEN
The importance of evaluating the cardiotoxicity potential of common chemicals as well as new drugs is increasing as a result of the development of animal alternative test methods using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Bisphenol A (BPA), which is used as a main material in plastics, is known as an endocrine-disrupting chemical, and recently reported to cause cardiotoxicity through inhibition of ion channels in CMs even with acute exposure. Accordingly, the need for the development of alternatives to BPA has been highlighted, and structural analogues including bisphenol AF, C, E, F, and S have been developed. However, cardiotoxicity data for analogues of bisphenol are not well known. In this study, in order to evaluate the cardiotoxicity potential of analogues, including BPA, a survival test of hiPSC-CMs and a dual-cardiotoxicity evaluation based on a multi-electrode array were performed. Acute exposure to all bisphenol analogues did not affect survival rate, but spike amplitude, beat period, and field potential duration were decreased in a dose-dependent manner in most of the bisphenols except bisphenol S. In addition, bisphenols, except for bisphenol S, reduced the contractile force of hiPSC-CMs and resulted in beating arrest at high doses. Taken together, it can be suggested that the developed bisphenol analogues could cause cardiotoxicity even with acute exposure, and it is considered that the application of the MEA-based dual-cardiotoxicity evaluation method can be an effective help in the development of safe alternatives.
Asunto(s)
Compuestos de Bencidrilo , Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Animales , Humanos , Cardiotoxicidad/etiología , Células Madre Pluripotentes Inducidas/fisiología , Fenoles/toxicidadRESUMEN
Beyond single cell two-dimensional (2D) culture, research on organoids that can mimic human organs is rapidly developing. However, there are still problems in commercialization and joint research using organoids due to the lack of technology to safely store organoids. Since organoids are 3D complex structures with a certain size (0.1-5 mm) beyond the size of cells, the conventional cell-level cryopreservation method using cryoprotectant (CPA) cannot overcome the damage caused by volume change due to osmotic pressure difference and ice nucleation. Herein, we attempted to solve such limitations by applying a nanowarming system using CPA with high cell permeability and Fe3 O4 nanoparticles. By performing beat rate measurement, histological analysis, contractility analysis, and multi-electrode array, it was verified that the developed method could significantly improve functional recovery and survival of heart organoids after freezing and thawing. In this study, we demonstrated a successful organoid cryopreservation method based on a Fe3 O4 nanowarming system. The developed technology will provide clues to the field of tissue cryopreservation and spur the application of organoids.
Asunto(s)
Criopreservación , Nanopartículas , Humanos , Criopreservación/métodos , Congelación , Crioprotectores/farmacología , OrganoidesRESUMEN
As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.
RESUMEN
Metal nanomaterials are highly valued for their enhanced surface area and electrochemical properties, which are crucial for energy devices and bioelectronics. However, their practical applications are often limited by challenges, such as scalability and dimensional constraints. In this study, we developed a synthesis method for highly porous Ag-Au core-shell nanowire foam (AACNF) using a one-pot process based on a simultaneous nanowelding synthesis method. The unique characteristics of AACNF as metal-based electrodes show the lowest density among metal-based electrodes while demonstrating high electrical conductivity (99.33-753.04 S/m) and mechanical stability. The AACNF's excellent mass transport properties enable multiscale hierarchical incorporation with functional materials including polymeric precursors and living cells. The enhanced mechanical stability at the nanowelded junctions allows AACNF-hydrogel composites to exhibit large stretching (â¼700%) and 10,000 times higher electrical conductivity than hydrogel-nanowire composites without the junction. Large particles in the 1-10 µm scale, including fibroblast cells and exoelectrogenic microbes, are also successfully incorporated with AACNF. AACNF-based microbial fuel cells show high power density (â¼330.1 W/m3) within the optimal density range. AACNF's distinctive ability to form a hierarchical structure with substances in various scales showcases its potential for advanced energy devices and biohybrid electrodes in the future.