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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Mar 26, 2015; 7(2): 329-342
Published online Mar 26, 2015. doi: 10.4252/wjsc.v7.i2.329
Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes
Patrizia Dell’Era, Patrizia Benzoni, Elisabetta Crescini, Matteo Valle, Er Xia, Antonella Consiglio, Maurizio Memo
Patrizia Dell’Era, Patrizia Benzoni, Elisabetta Crescini, Matteo Valle, Er Xia, Antonella Consiglio, Fibroblast Reprogramming Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Maurizio Memo, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Author contributions: All the authors contributed to the research, in the preparation of the paper, and in the following revision; Dell’Era P was also responsible for designing and editing the review.
Supported by Roberto and Fabiana Marai.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Patrizia Dell’Era, PhD, Fibroblast Reprogramming Unit, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. patrizia.dellera@unibs.it
Telephone: +39-03-03717539 Fax: +39-03-03717539
Received: July 29, 2014
Peer-review started: July 29, 2014
First decision: October 14, 2014
Revised: October 27, 2014
Accepted: November 17, 2014
Article in press: November 19, 2014
Published online: March 26, 2015
Processing time: 234 Days and 6.6 Hours
Abstract

Causative mutations and variants associated with cardiac diseases have been found in genes encoding cardiac ion channels, accessory proteins, cytoskeletal components, junctional proteins, and signaling molecules. In most cases the functional evaluation of the genetic alteration has been carried out by expressing the mutated proteins in in-vitro heterologous systems. While these studies have provided a wealth of functional details that have greatly enhanced the understanding of the pathological mechanisms, it has always been clear that heterologous expression of the mutant protein bears the intrinsic limitation of the lack of a proper intracellular environment and the lack of pathological remodeling. The results obtained from the application of the next generation sequencing technique to patients suffering from cardiac diseases have identified several loci, mostly in non-coding DNA regions, which still await functional analysis. The isolation and culture of human embryonic stem cells has initially provided a constant source of cells from which cardiomyocytes (CMs) can be obtained by differentiation. Furthermore, the possibility to reprogram cellular fate to a pluripotent state, has opened this process to the study of genetic diseases. Thus induced pluripotent stem cells (iPSCs) represent a completely new cellular model that overcomes the limitations of heterologous studies. Importantly, due to the possibility to keep spontaneously beating CMs in culture for several months, during which they show a certain degree of maturation/aging, this approach will also provide a system in which to address the effect of long-term expression of the mutated proteins or any other DNA mutation, in terms of electrophysiological remodeling. Moreover, since iPSC preserve the entire patients’ genetic context, the system will help the physicians in identifying the most appropriate pharmacological intervention to correct the functional alteration. This article summarizes the current knowledge of cardiac genetic diseases modelled with iPSC.

Keywords: Cardiomyopathies; Cardiac arrhythmias; Induced pluripotent stem cells; Human cardiomyocytes

Core tip: This paper revises the cardiac genetic diseases that have been modeled so far using the technology that starts from patient somatic cells, reprogram their fate to a pluripotent state, and then proceed to cardiomyocyte differentiation. We will describe the main steps of this procedure, from pluripotent stem cells to mature cardiomyocytes, and we will discuss the main features linked to the different cardiac pathologies that this model recapitulate in a cell culture dish.