Cardiac disease modeling using induced pluripotent stemcell-derived human cardiomyocytes

• 作者: Patrizia Dell’Era Patrizia Benzoni Elisabetta Crescini Matteo Valle Er Xia Antonella Consiglio Maurizio Memo
• 来源期刊: 世界干细胞杂志：英文版（电子版）
• 学科: 医学
• 关键词: CARDIOMYOPATHIES Cardiac ARRHYTHMIAS INDUCED PLURIPOTENT stem cells Human cardiomyocytes
• 年，卷（期）: 2015,（2）
• 页码范围: 329-342
• 页数: 14页
• 分类号: R

摘要

Causative mutations and variants associated with cardiacdiseases have been found in genes encoding cardiac ionchannels, accessory proteins, cytoskeletal components,junctional proteins, and signaling molecules. In mostcases the functional evaluation of the genetic alterationhas been carried out by expressing the mutated proteinsin in-vitro heterologous systems. While these studieshave provided a wealth of functional details that havegreatly enhanced the understanding of the pathologicalmechanisms, it has always been clear that heterologousexpression of the mutant protein bears the intrinsiclimitation of the lack of a proper intracellular environmentand the lack of pathological remodeling. The resultsobtained from the application of the next generationsequencing technique to patients suffering from cardiacdiseases have identified several loci, mostly in non-codingDNA regions, which still await functional analysis. Theisolation and culture of human embryonic stem cells hasinitially provided a constant source of cells from whichcardiomyocytes （CMs） can be obtained by differentiation.Furthermore, the possibility to reprogram cellular fateto a pluripotent state, has opened this process to thestudy of genetic diseases. Thus induced pluripotentstem cells （iPSCs） represent a completely new cellularmodel that overcomes the limitations of heterologousstudies. Importantly, due to the possibility to keepspontaneously 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 whichto address the effect of long-term expression of themutated proteins or any other DNA mutation, in termsof electrophysiological remodeling. Moreover, sinceiPSC preserve the entire patients＇ genetic context, thesystem will help the physicians in identifying the mostappropriate pharmacological intervention to correct thefunctional alteration. This article summarizes the currentknowledge of cardiac genetic diseases modelled withiPSC.