1. Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.
- Author
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Smith JGW, Owen T, Bhagwan JR, Mosqueira D, Scott E, Mannhardt I, Patel A, Barriales-Villa R, Monserrat L, Hansen A, Eschenhagen T, Harding SE, Marston S, and Denning C
- Subjects
- Arrhythmias, Cardiac pathology, Arrhythmias, Cardiac physiopathology, CRISPR-Cas Systems genetics, Calcium metabolism, Calcium Signaling, Cardiomyopathy, Hypertrophic physiopathology, Gene Editing, Heart Defects, Congenital pathology, Heart Defects, Congenital physiopathology, Humans, Induced Pluripotent Stem Cells metabolism, Myocardial Contraction, Myocytes, Cardiac metabolism, Tissue Engineering, Actins genetics, Cardiomyopathy, Hypertrophic pathology, Induced Pluripotent Stem Cells pathology, Mutation genetics, Myocytes, Cardiac pathology
- Abstract
Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca
2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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