Extending Human Induced Pluripotent Stem Cell Technology to Infectious Diseases

Abstract

Downloaded from Circulation ResearchAugust 29, 2014The study by Sharma et al 11 extends the field of iPSC-based cardiovascular disease models to infectious diseases. To date, genetically caused channelopathies and cardiomyopathies have been the focus of this emerging technology.12 Although animal models are an important fundament of cardiovascular research, it is often desirable to investigate disease mechanisms or drug effects in human cells to exclude that species differences result in wrong conclusions. Primary human myocardial tissue can be obtained only by invasive procedures and cannot be propagated or kept in culture for a long time period. Cardiomyocytes derived from iPSC are one possible solution to these obstacles because they represent a theoretically unlimited source of human cardiomyocytes. In their study, Sharma et al 11 have shown that, in the case of coxsackievirus B3-mediated myocarditis, this system can be used not only to model the disease in vitro but also as a platform to evaluate drugs that interfere with the disease, and-by gene expression analysis-to investigate the mechanism of drug action further (Figure [B]).In principle, iPSC technology would offer the possibility to investigate other important aspects of viral myocarditis. It is well known that the susceptibility to viral myocarditis is genetically determined. 13 The progression of viral myocarditis to dilated cardiomyopathy may be also influenced by genetic susceptibility factors.14 By deriving iPSCs not only from healthy individuals but also from patients affected by viral myocarditis (assuming their susceptibility to the disease) and from patients who have developed dilated cardiomyopathy after viral myocarditis, it might be possible to elucidate the molecular mechanisms of this susceptibility further. Knowledge of the signal transduction pathways that confer resistance to virus-mediated myocardial damage might inform the development of specific drugs to prevent the potentially devastating consequences of this disease.Nevertheless, it should be noted that the study by Sharma et al 11 models only 1 aspect of viral myocarditis-the cellautonomous interaction between the cardiomyocytes and the virus particles. Earlier studies in experimental models have suggested 3 still controversial mechanisms by which viral myocarditis causes damage to the heart: (1) direct virus-induced cardiomyocyte injury; (2) destruction of the myocardium by infiltrating immune cells targeting virus-infected cardiomyocytes; (3) autoimmune-mediated destruction of cardiac cells by circulating autoantibodies and autoreactive immune cells. 15In its present state, the iPSC-derived experimental myocarditis model only allows investigation of the first aspect. It may be an advantage to be able to study the virus-cardiomyocyte interaction in an isolated fashion. However, to gain a complete picture of the pathogenesis of viral myocarditis, human disease models that also capture the other above-mentioned aspects of the disease will be necessary in the future. Acknowled...

MicroRNA-19b Downregulates Gap Junction Protein Alpha1 and Synergizes with MicroRNA-1 in Viral Myocarditis

“…In comparison, HL-1 cells are an immortalized mouse cardiac cell line derived from a tumor lineage that does not reflect adult human cardiomyocytes [ 25 ]. As reported by Sinnecker et al ., hiPSCs-CMs could provide a novel platform for studying the mechanisms of CVB 3 -induced viral myocarditis [ 26 ]. Hence, hiPSCs-CMs were utilized to study the functional role of miR-19b in vitro .…”