Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand?

Sebastian Diecke,Ian Y Chen,Antje D Ebert,Joseph C Wu

doi:10.15252/emmm.201504395

Abstract

Heart disease remains a leading cause of mortality and a major worldwide healthcare burden. Recent advances in stem cell biology have made it feasible to derive large quantities of cardiomyocytes for disease modeling, drug development, and regenerative medicine. The discoveries of reprogramming and transdifferentiation as novel biological processes have significantly contributed to this paradigm. This review surveys the means by which reprogramming and transdifferentiation can be employed to generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and induced cardiomyocytes (iCMs). The application of these patient-specific cardiomyocytes for both in vitro disease modeling and in vivo therapies for various cardiovascular diseases will also be discussed. We propose that, with additional refinement, human disease-specific cardiomyocytes will allow us to significantly advance the understanding of cardiovascular disease mechanisms and accelerate the development of novel therapeutic options.

Highlights

Despite advances in medical therapy, cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide
Animal models have provided indispensable insights into systemic whole-organ function in vivo as well as in vitro disease mechanisms (Fiedler et al, 2014; Houser et al, 2012; Duncker et al, 2015), not all findings from research on rodent cardiomyocytes can be translated to human cardiomyocytes at the cellular and molecular levels
Human induced pluripotent stem cells (iPSCs) present the unprecedented opportunity to study disease-specific differences in a patient-specific manner, taking into account individual drug responses within a patient population. The validity of this approach is exemplified by the successful application of human iPSCs to model LEOPARD syndrome (Carvajal-Vergara et al, 2010), Timothy syndrome (Yazawa et al, 2011), long QT syndrome (Moretti et al, 2010; Itzhaki et al, 2011; Wang et al, 2014), arrhythmogenic right ventricular dysplasia (ARVD) (Kim et al, 2013; Asimaki et al, 2014), familial dilated cardiomyopathy (DCM; Sun et al, 2012), familial hypertrophic cardiomyopathy

Summary

Introduction

Despite advances in medical therapy, cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide. To understand the molecular and genetic determinants of CVD, advanced genome editing techniques are required to study genotype/phenotype relationships and to allow for the correction of patient-specific mutations in human iPSCs (Wang et al, 1995; Chen et al, 1998; Schwartz et al, 2000; Benson et al, 2003; Fig 1).

Results

Conclusion