Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits
File(s)
Published version
Author(s)
Type
Journal Article
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 Ca2+ 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.
Date Issued
2018-11-13
Date Acceptance
2018-11-01
Citation
Stem Cell Reports, 2018, 11 (5), pp.1226-1243
ISSN
2213-6711
Publisher
Elsevier (Cell Press)
Start Page
1226
End Page
1243
Journal / Book Title
Stem Cell Reports
Volume
11
Issue
5
Copyright Statement
© 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor
British Heart Foundation
British Heart Foundation
Grant Number
FS/13/54/30642
RM/17/1/33377
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Cell Biology
PLURIPOTENT STEM-CELLS
ALPHA-CARDIAC ACTIN
ENGINEERED HEART-TISSUE
ABERRANT CA2+ RELEASE
DILATED CARDIOMYOPATHY
GENE-EXPRESSION
CARDIOMYOCYTES
MOUSE
MECHANISM
CHILDREN
arrhythmia
cardiomyopathy
contractile function
hypertrophy
Publication Status
Published
Date Publish Online
2018-11-01