Evaluation of the cardiotoxicity potential of bisphenol analogues in human induced pluripotent stem cells derived cardiomyocytes.

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.

Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate.

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.

Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental contact urticaria by regulating the functions of mast cells and T cells.

Contact urticaria (CU) is an inflammatory skin disorder triggered by specific substances upon skin contact, leading to immediate acute or chronic manifestations characterized by swelling and redness. While mesenchymal stem cells (MSCs) are increasingly recognized for their therapeutic potential in immune diseases, research on the efficacy and mechanisms of stem cell therapy for urticaria remains scarce. This study investigates the regulatory role of embryonic-stem-cell-derived multipotent MSCs (M-MSCs) administered in a CU mouse model. Therapeutic effects of M-MSC administration were assessed in a Trimellitic anhydride-induced contact urticaria model, revealing significant inhibition of urticarial reactions, including ear swelling, itchiness, and skin lesion. Moreover, M-MSC administration exerted control over effector T cell activities in major lymphoid and peripheral tissues, while also suppressing mast cell degranulation in peripheral tissues. Notably, the inhibitory effects mediated by M-MSCs were found to be TGF-ß-dependent. Our study demonstrates the capacity of M-MSCs to regulate contact urticaria in a murine model, harmonizing the activation of inflammatory T cells and mast cells. Additionally, we suggest that TGF-ß derived from M-MSCs could play a pivotal role as an inhibitory mechanism in contact urticaria.