Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as an In Vitro Model for Coxsackievirus B3–Induced Myocarditis and Antiviral Drug Screening Platform

1 MicroRNA-181b inhibits vascular inflammation and atherosclerosis in mice, report Sun et al.Atherosclerosis is a chronic inflammatory vascular disease that is in part driven by the activation of the transcription factor NF-κB. In vascular endothelial cells, oxidized low-density lipoproteins, angiotensin II and other pro-atherogenic factors activate NF-κB. These factors promote the transfer of NFkB from the cytoplasm to the nucleus where it increases the transcription of pro-inflammatory genes. Recently, miR-181b was found to repress importin-α3, the protein responsible for transferring NF-κB to the nucleus. But whether this miR could actually suppress atherosclerosis was unknown. This prompted Sun and colleagues to inject atherosclerosis-prone mice with a version of miR-181b. They found that miR-181b reduced NF-κB activity as well as the expression of importin-α in the aortic arches of the mice. Importantly, atherosclerotic lesion formation was also reduced, and the lesions contained fewer macrophages and T cells. Interestingly, the team also found that patients with coronary artery disease had reduced levels of miR-181b in their blood. Taken together these results indicate that increasing miR-181b levels in patients could be a potential therapy for diminishing atherogenesis. A non-fatal heart attack often leads to progressive tissue damage that results in heart failure. Indeed, despite recent advances, Lasting Effects of AAV1/SERCA2a in Heart Failure

“…Human iPSC-CMs as a Model for Viral Myocarditis (p 556) 50 Heart cells derived from human induced pluripotent stem cells can be used to study viral infection, report Sharma et al…”

Section: Mutations In Stap1 Associatementioning

confidence: 99%

Circulation Research “In This Issue” Anthology

Williams¹

2015

“…In this issue of Circulation Research, Sharma et al 15 used human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) as an in vitro model for CVB3-induced myocarditis and antiviral drug screening platform. Since the discovery of human iPS in 2007 by Takahashi and Yamanaka 16 and Yu et al, 17 that is, the reprogramming of human somatic skin fibroblasts to pluripotency via the ectopic expression of the transcription factors Oct4, Sox2 in combination with either Krüppel-like factor 4 and Myc or Nanog and Lin28, human iPS have been used as a source of cardiac regeneration 18 and as tool for modeling cardiac disease.…”

Section: Article See P 556mentioning

confidence: 99%

Lack in Treatment Options for Virus-Induced Inflammatory Cardiomyopathy

Linthout

Tschöpe

Schultheiss

2014

Downloaded from Van Linthout et al iPSCs and Virus-Induced Inflammatory Cardiomyopathy 541of human iPS-CM and CVB3 copy number in endomyocardial biopsies of corresponding patients are desired. As such, iPS-CM might have a prognostic value, only in relation to endomyocardial biopsies, the diagnostic gold standard. 24 It should also be recognized that via using iPS-CM as antiviral drug platform, only 1 aspect of the viral pathogenesis, that is, the direct cytotoxic effect of CVB3 in cardiomyocytes, is taken into account and not the systemic immune effects, 9 which are triggered by the virus. In addition, it should be addressed that concentrations of antiviral drugs tested on iPS-CM combining efficacy with absence of toxicity cannot necessarily be extrapolated to the human in vivo condition. Last, but most importantly, the prevalence of enteroviral-positive patients is relatively low today. Predominantly, patients with inflammatory cardiomyopathy have Parvovirus B19-positive endomyocardial biopsies.25 In contrast to enteroviruses for which immunomodulation with interferon might be a therapeutic option, there are no specific antiviral strategies for Parvovirus B19 identified so far. Hereby, it is important to take into account that Parvovirus B19 leads, in contrast to enteroviruses, to a predominant endothelial infection. 26,27 Therefore, it will be a further challenge and need to set up iPS-derived endothelial cells and to screen for anti-Parvovirus B19 pharmaca in the near future, too. AcknowledgmentsThis study is supported by the German Center for Cardiovascular Research (DZHK) to S. Van Linthout and C. Tschöpe. DisclosuresNone. Nature. 2011;471:225-229. 22 References

“…Such models comprise immortalized, proliferative cell lines, such as HEK293T and HeLa cells, or genetically susceptible mice that are infected with coxsackievirus B3. [8][9][10] In this issue of Circulation Research, Sharma et al 11 report on a different approach at modeling viral myocarditis. They obtained either skin fibroblasts or mononuclear blood cells from healthy individuals and, by viral transduction with a specific cocktail of reprogramming factors, reprogrammed them to induced pluripotent stem cells (iPSCs).…”

Section: Article See P 556mentioning

confidence: 99%

“…The 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.…”

Section: Circulation Research August 29 2014mentioning

confidence: 99%

“…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]). …”

Section: Circulation Research August 29 2014mentioning

confidence: 99%

See 1 more Smart Citation

Extending Human Induced Pluripotent Stem Cell Technology to Infectious Diseases

Sinnecker

Laugwitz

Moretti

2014

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...