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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, Vol. 11, No. 5, 13.11.2018, p. 1226-1243.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 & Denning, C 2018, 'Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits', STEM CELL REP, vol. 11, no. 5, pp. 1226-1243. https://doi.org/10.1016/j.stemcr.2018.10.006

APA

Smith, J. G. W., Owen, T., Bhagwan, J. R., Mosqueira, D., Scott, E., Mannhardt, I., Patel, A., Barriales-Villa, R., Monserrat, L., Hansen, A., Eschenhagen, T., Harding, S. E., Marston, S., & Denning, C. (2018). Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits. STEM CELL REP, 11(5), 1226-1243. https://doi.org/10.1016/j.stemcr.2018.10.006

Vancouver

Smith JGW, Owen T, Bhagwan JR, Mosqueira D, Scott E, Mannhardt I et al. Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits. STEM CELL REP. 2018 Nov 13;11(5):1226-1243. https://doi.org/10.1016/j.stemcr.2018.10.006

Bibtex

@article{606328f741434e7ab61eb7d4806be2bb,
title = "Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTCI E99K Mutation Unveil Differential Functional Deficits",
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.",
keywords = "Journal Article",
author = "Smith, {James G W} and Thomas Owen and Bhagwan, {Jamie R} and Diogo Mosqueira and Elizabeth Scott and Ingra Mannhardt and Asha Patel and Roberto Barriales-Villa and Lorenzo Monserrat and Arne Hansen and Thomas Eschenhagen and Harding, {Sian E} and Steve Marston and Chris Denning",
note = "Copyright {\textcopyright} 2018 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = nov,
day = "13",
doi = "10.1016/j.stemcr.2018.10.006",
language = "English",
volume = "11",
pages = "1226--1243",
journal = "STEM CELL REP",
issn = "2213-6711",
publisher = "Cell Press",
number = "5",

}

RIS

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 -