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Personalized medicine and the role of induced pluripotent stem cells

Marcel A.G. van der Heyden, Malin K.B. Jonsson
DOI: http://dx.doi.org/10.1093/cvr/cvs242 395-396 First published online: 20 July 2012

This editorial refers to ‘Disease characterization using LQTS-specific induced pluripotent stem cells’ by T. Egashira et al., pp. 419–429, this issue.

Nearly a decade after the first description of obtaining and differentiating human embryonic stem cells in 1998,1 the reports in 2007 of induced pluripotent stem cells (iPSCs) from human tissues2,3 heralded a second era of human stem cell research that currently delivers many interesting new findings. iPSCs are normally produced by overexpression of the OCT3/4, SOX2, KLF4, and c-MYC genes in human skin cells, followed by culturing techniques initially developed for keeping human embryonic stem cells undifferentiated. Subsequently, the iPSCs that now express a number of stem cell markers can be differentiated into the cell type of interest by dedicated methods that often include a phase of embryoid body formation. Two major applications of iPSCs were foreseen immediately. The first was in regenerative medicine in which autologous transplantation might come within reach. In cardiac research, a number of innovations have arisen that may prove to be important for future therapies, like high-purity enrichment of specific cardiovascular cell types from iPSCs4 and direct reprogramming of resident cells into cardiomyocytes in vivo, as has been shown recently in mice.5 The latter shows that the heart can regenerate without the need for transplantation of exogenous cells. The second application, in which progress is already achieving clinical significance, is the development of new human disease models that by definition are personalized. Lee et al.6 isolated iPSCs from familial dysautonomia patients and demonstrated that upon differentiation into peripheral neurons the cells phenocopied several characteristics of the human disease. Moreover, they applied the cells for testing the outcomes of drug therapy aimed at reversing the aberrant splicing seen in patients. In cardiac arrhythmia research, several interesting studies have been published since on inherited long-QT syndrome (LQTS).7,8

In this issue of Cardiovascular Research, Egashira et al.9 report the results of their studies on generating iPSCs from an LQTS1 patient with an apparent de novo mutation in KCNQ1, its functional analysis with respect to the disease phenotype and its underlying mechanisms, and the foreseen patient's response to drug therapy. In short, the authors derived iPSCs from a skin biopsy of a 13-year-old boy who experienced, and survived, sudden cardiac arrest during exercise. His ECG showed marked QT prolongation while those of his relatives were normal. Sequencing of LQTS-associated genes provided evidence for a heterozygous mutation in the KCNQ1 gene which encodes the α-subunit of the slow component of the delayed rectifier channel, IKs. Upon differentiation into cardiomyocytes, cells recapitulated the disease phenotype, showing prolonged repolarization times and isoproterenol-induced arrhythmias. As expected for this LQTS subtype, pharmacological IKs blockade did not further prolong repolarization. IKr blockade, however, further prolonged repolarization times and induced arrhythmic events. Also, IK1 inhibition prolonged repolarization but was not associated with pro-arrhythmia. This outcome of pharmaceutical interventions may be important for future decisions on drug regimens with respect to adverse effects in this particular patient and his possible future children. Interestingly, propranolol application blunted the isoproterenol-induced early afterdepolarizations and ventricular tachycardia-like events, providing a strong fundament for the already initiated β-blockade therapy. Finally, a forward KCNQ1 trafficking defect appeared to underlie the reduced IKs density. Effects on trafficking of repolarizing ion channels, either due to genetic or drug-induced causes, are becoming recognized as an important factor in pro-arrhythmia.10 Their recapitulation in iPSC-derived cardiomyocytes, as demonstrated here, offers valuable tools for developing therapies to relieve trafficking defects in the context of a functional cardiomyocyte.

Egashira et al. strongly advocate the use of iPSCs for personalized medicine, but it is unclear what impact their analysis of the iPSCs obtained had on this 13-year-old boy's medical treatment. The authors acknowledge that current methods for iPSC production and analysis have to be improved with respect to the time frame and costs. At present, established laboratories need ∼2–4 months to transform somatic human cells into iPSC-derived cardiomyocytes,8 making it a time-consuming and expensive exercise. In addition, addressing other, still remaining challenges such as improving the maturity of iPSC-derived cardiomyocytes and producing more homogeneous cultures in a standardized and worldwide manner, enabling relatively cheap and large-scale production, will be crucial to introducing the use of iPSCs into routine clinical applications.

In a parallel area of research, geneticists and their companies battle for the first ‘one-thousand dollar genome’, meaning that a person's entire genome can be sequenced for a maximum cost of $1000 within a short time.11,12 Soon this hurdle will be surmounted, and this technological development will provide a wealth of personalized genetic information for millions of patients and their diseases and will undoubtedly yield numerous new gene–disease associations in the near future. Nevertheless, independent of how strong the geno–phenotype correlations will eventually be, we think that a functional readout system seems essential to providing personalized medicine with the strong foundation it needs in clinical practice. As shown in this elegant study of Egashira et al., iPSCs can provide such a readout system for cardiac electrophysiology. In analogy, the race for the ‘one-thousand dollar iPSC’ should now start to keep up the required pace.

Funding

This work was supported by EU's FP7 Initial Training Network ‘CardioNeT’.

Conflict of interest: M.J. is an employee of Cellartis AB.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

References