Optimizing the Use of iPSC-CMs for Cardiac Regeneration in Animal Models

SIMPLE SUMMARY: In 2006, the first induced pluripotent stem cells were generated by reprogramming skin cells. Induced pluripotent stem cells undergo fast cell division, can differentiate into many different cell types, can be patient-specific, and do not raise ethical issues. Thus, they offer great promise as in vitro disease models, drug toxicity testing platforms, and for autologous tissue regeneration. Heart failure is one of the major causes of death worldwide. It occurs when the heart cannot meet the body’s metabolic demands. Induced pluripotent stem cells can be differentiated into cardiac myocytes, can form patches resembling native cardiac tissue, and can engraft to the damaged heart. However, despite correct host/graft coupling, most animal studies demonstrate an arrhythmogenicity of the engrafted tissue and variable survival. This is partially because of the heterogeneity and immaturity of the cells. New evidence suggests that by modulating induced pluripotent stem cells-cardiac myocytes (iPSC-CM) metabolism by switching substrates and changing metabolic pathways, you can decrease iPSC-CM heterogeneity and arrhythmogenicity. Novel culture methods and tissue engineering along with animal models of heart failure are needed to fully unlock the potential of cardiac myocytes derived from induced pluripotent stem cells for cardiac regeneration. ABSTRACT: Heart failure (HF) is a common disease in which the heart cannot meet the metabolic demands of the body. It mostly occurs in individuals 65 years or older. Cardiac transplantation is the best option for patients with advanced HF. High numbers of patient-specific cardiac myocytes (CMs) can be generated from induced pluripotent stem cells (iPSCs) and can possibly be used to treat HF. While some studies found iPSC-CMS can couple efficiently to the damaged heart and restore cardiac contractility, almost all found iPSC-CM transplantation is arrhythmogenic, thus hampering the use of iPSC-CMs for cardiac regeneration. Studies show that iPSC-CM cultures are highly heterogeneous containing atrial-, ventricular- and nodal-like CMs. Furthermore, they have an immature phenotype, resembling more fetal than adult CMs. There is an urgent need to overcome these issues. To this end, a novel and interesting avenue to increase CM maturation consists of modulating their metabolism. Combined with careful engineering and animal models of HF, iPSC-CMs can be assessed for their potential for cardiac regeneration and a cure for HF.