As the quote says, “If power is defined as the ability to do anything and create anything, then the stem cell is the most powerful known life force.” In agreement with the quote, the collective efforts made by the scientific community to implement the 3Rs (Replace, Reduce, and Refine) in toxicology have opened a plethora of opportunities in nonanimal models, and one such nonanimal research modeling tool is “stem cells.” During the SOT 61st Annual Meeting and ToxExpo, Dr. Marie Fortin, Associate Director of Toxicology from Jazz Pharmaceuticals, introduced the biology of human-induced pluripotent stem cells as an innovative approach in science for toxicological studies. Her presentation, entitled, “Studying Drug-Induced Cardiotoxicity Is Complicated: How Human Induced Pluripotent Stem Cells and In Vitro Biomarkers Helped Solve This Challenge,” focused on using human-induced pluripotent stem cell (hiPSC)–derived cardiomyocytes as an alternative approach to investigate cardiotoxicity.
Adverse drug reactions (ADR) are the harmful side effects of compounds that may occur after acute or chronic exposure, which is a major roadblock to drug safety. The clinical utility of many drugs is limited due to their known adverse effects on cardiovascular function. One such drug class is anthracyclines, which are widely used as chemotherapeutic agents in the treatment of leukemia and aggressive forms of breast cancer. Unfortunately, the efficacy of anthracyclines in treating cancer is limited by cumulative dose-dependent cardiotoxicity, which can cause drug-induced toxicity such as arrhythmias and irreversible heart failure. The scientific community has devoted greater attention to developing formulations that would mitigate cardiotoxicity and demonstrate greater clinical benefit.
It has been relatively difficult to compare the cardiotoxicity of different drugs or formulations using standard clinical or nonclinical models. Animal models are not sensitive enough, and species-specific differences in drug metabolism limit the value of preclinical in vivo studies. To overcome the limitations of animal models in assessing ADR, hiPSC-derived cardiomyocytes offer a more physiologically relevant model emulating many of the characteristics of healthy human cardiac muscle cells, such as gene and protein expression and rhythmic beating pattern.
Following a comprehensive overview of hiPSC-derived cardiomyocytes and their role in assessing anthracycline-induced cardiotoxicity, the audience engaged in a case study discussion where they discussed the advantages of hiPSC-derived cardiomyocytes, toxicological assays to assess cardiotoxicity, and why it is important to use in vitro methods to understand the safety profile of drugs.
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