Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits
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Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits. / Smith, James G W; Owen, Thomas; Bhagwan, Jamie R; Mosqueira, Diogo; Scott, Elizabeth; Mannhardt, Ingra; Patel, Asha; Barriales-Villa, Roberto; Monserrat, Lorenzo; Hansen, Arne; Eschenhagen, Thomas; Harding, Sian E; Marston, Steve; Denning, Chris.
in: STEM CELL REP, Jahrgang 11, Nr. 5, 13.11.2018, S. 1226-1243.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits
AU - Smith, James G W
AU - Owen, Thomas
AU - Bhagwan, Jamie R
AU - Mosqueira, Diogo
AU - Scott, Elizabeth
AU - Mannhardt, Ingra
AU - Patel, Asha
AU - Barriales-Villa, Roberto
AU - Monserrat, Lorenzo
AU - Hansen, Arne
AU - Eschenhagen, Thomas
AU - Harding, Sian E
AU - Marston, Steve
AU - Denning, Chris
N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2018/11/13
Y1 - 2018/11/13
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1016/j.stemcr.2018.10.006
DO - 10.1016/j.stemcr.2018.10.006
M3 - SCORING: Journal article
C2 - 30392975
VL - 11
SP - 1226
EP - 1243
JO - STEM CELL REP
JF - STEM CELL REP
SN - 2213-6711
IS - 5
ER -