Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy, characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific models, investigating underlying mechanisms, and optimizing therapy. Here we generated cardiomyocytes (CMs) from iPSCs derived from patients of a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to the control healthy individuals in the same family cohort, DCM iPSC-CMs exhibited altered Ca2+ handling, decreased contractility, and abnormal sarcomeric α-actinin distribution. When stimulated with β-adrenergic agonist, DCM iPSC-CMs showed characteristics of failure such as reduced beating rates, compromised contraction, and significantly more cells with abnormal sarcomeric α-actinin distribution. β-adrenergic blocker treatment and over-expression of sarcoplasmic reticulum Ca2+ ATPase (Serca2a) improved DCM iPSC-CMs function. Our study demonstrated that human DCM iPSC-CMs recapitulated to some extent the disease phenotypes morphologically and functionally, and thus can serve as a useful platform for exploring molecular and cellular mechanisms and optimizing treatment of this particular disease.

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

“…1b). Loss of Z-disk architecture was also evident in the DCM myocardium, a finding that is recapitulated in isolated cardiomyocytes derived from induced pluripotent stem cells in patients with DCM 17 . The interaction of ILK and SERCA-2a was further probed in ILK immunoprecipitates (IPs) from the hearts of mice with transgenic myocardial overexpression of wild-type ILK (ILK WT ) 15 , which revealed co-immunoprecipitation (co-IP) of ILK with SERCA-2a confirmed using mass spectrometry ( Supplementary Fig.…”

Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model

“…A previous study created a human DCM iPSC-derived cardiomyocyte model, which was generated from DCM patients carrying the TNNT2 mutation and from healthy controls without this mutation, in order to investigate relevant DCM mechanisms and potential drug therapy (13). As a result, the study discovered that, in comparison with the healthy control group, the iPSC-derived cardiomyocytes from DCM patients showed altered regulation of Ca 2+ and abnormal distribution of sarcomeric α-actin (13). Despite these valuable findings, gene alterations in DCM cardiomyocytes, as well as regulatory correlations of these genes were not considered.…”

Live Fluorescent RNA-Based Detection of Pluripotency Gene Expression in Embryonic and Induced Pluripotent Stem Cells of Different Species

“…They have been used to unravel disease-related molecular mechanisms (disease modeling) in particular for genetically inherited diseases [8][9][10]. Since they harbor the patient-specific genetic background they allow a customized screening of the efficiency of drugs that might be used as therapeutic agents [11][12][13].…”