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CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy

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CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. / Mosqueira, Diogo; Mannhardt, Ingra; Bhagwan, Jamie; Lis-Slimak, Katarzyna; Katili, Puspita; Scott, Elizabeth; Hassan, Mustafa; Prondzynski, Maksymilian; Harmer, Stephen; Tinker, Andrew; Smith, James G W; Carrier, Lucie; Williams, P M; Gaffney, Daniel; Eschenhagen, Thomas; Hansen, Arne; Denning, Chris N.

In: EUR HEART J, Vol. 39, No. 43, 14.11.2018, p. 3879-3892.

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

Harvard

Mosqueira, D, Mannhardt, I, Bhagwan, J, Lis-Slimak, K, Katili, P, Scott, E, Hassan, M, Prondzynski, M, Harmer, S, Tinker, A, Smith, JGW, Carrier, L, Williams, PM, Gaffney, D, Eschenhagen, T, Hansen, A & Denning, CN 2018, 'CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy', EUR HEART J, vol. 39, no. 43, pp. 3879-3892. https://doi.org/10.1093/eurheartj/ehy249

APA

Mosqueira, D., Mannhardt, I., Bhagwan, J., Lis-Slimak, K., Katili, P., Scott, E., Hassan, M., Prondzynski, M., Harmer, S., Tinker, A., Smith, J. G. W., Carrier, L., Williams, P. M., Gaffney, D., Eschenhagen, T., Hansen, A., & Denning, C. N. (2018). CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. EUR HEART J, 39(43), 3879-3892. https://doi.org/10.1093/eurheartj/ehy249

Vancouver

Mosqueira D, Mannhardt I, Bhagwan J, Lis-Slimak K, Katili P, Scott E et al. CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. EUR HEART J. 2018 Nov 14;39(43):3879-3892. https://doi.org/10.1093/eurheartj/ehy249

Bibtex

@article{d68cc0ea6e6d4a169be84f463109bfeb,
title = "CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy",
abstract = "Aims: Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM.Methods and results: CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines. Isogenic sets were differentiated to hPSC-CMs for high-throughput, non-subjective molecular and functional assessment using 12 approaches in 2D monolayers and/or 3D engineered heart tissues. Although immature, edited hPSC-CMs exhibited the main hallmarks of HCM (hypertrophy, multi-nucleation, hypertrophic marker expression, sarcomeric disarray). Functional evaluation supported the energy depletion model due to higher metabolic respiration activity, accompanied by abnormalities in calcium handling, arrhythmias, and contraction force. Partial phenotypic rescue was achieved with ranolazine but not omecamtiv mecarbil, while RNAseq highlighted potentially novel molecular targets.Conclusion: Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.",
author = "Diogo Mosqueira and Ingra Mannhardt and Jamie Bhagwan and Katarzyna Lis-Slimak and Puspita Katili and Elizabeth Scott and Mustafa Hassan and Maksymilian Prondzynski and Stephen Harmer and Andrew Tinker and Smith, {James G W} and Lucie Carrier and Williams, {P M} and Daniel Gaffney and Thomas Eschenhagen and Arne Hansen and Denning, {Chris N}",
year = "2018",
month = nov,
day = "14",
doi = "10.1093/eurheartj/ehy249",
language = "English",
volume = "39",
pages = "3879--3892",
journal = "EUR HEART J",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "43",

}

RIS

TY - JOUR

T1 - CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy

AU - Mosqueira, Diogo

AU - Mannhardt, Ingra

AU - Bhagwan, Jamie

AU - Lis-Slimak, Katarzyna

AU - Katili, Puspita

AU - Scott, Elizabeth

AU - Hassan, Mustafa

AU - Prondzynski, Maksymilian

AU - Harmer, Stephen

AU - Tinker, Andrew

AU - Smith, James G W

AU - Carrier, Lucie

AU - Williams, P M

AU - Gaffney, Daniel

AU - Eschenhagen, Thomas

AU - Hansen, Arne

AU - Denning, Chris N

PY - 2018/11/14

Y1 - 2018/11/14

N2 - Aims: Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM.Methods and results: CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines. Isogenic sets were differentiated to hPSC-CMs for high-throughput, non-subjective molecular and functional assessment using 12 approaches in 2D monolayers and/or 3D engineered heart tissues. Although immature, edited hPSC-CMs exhibited the main hallmarks of HCM (hypertrophy, multi-nucleation, hypertrophic marker expression, sarcomeric disarray). Functional evaluation supported the energy depletion model due to higher metabolic respiration activity, accompanied by abnormalities in calcium handling, arrhythmias, and contraction force. Partial phenotypic rescue was achieved with ranolazine but not omecamtiv mecarbil, while RNAseq highlighted potentially novel molecular targets.Conclusion: Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.

AB - Aims: Sarcomeric gene mutations frequently underlie hypertrophic cardiomyopathy (HCM), a prevalent and complex condition leading to left ventricle thickening and heart dysfunction. We evaluated isogenic genome-edited human pluripotent stem cell-cardiomyocytes (hPSC-CM) for their validity to model, and add clarity to, HCM.Methods and results: CRISPR/Cas9 editing produced 11 variants of the HCM-causing mutation c.C9123T-MYH7 [(p.R453C-β-myosin heavy chain (MHC)] in 3 independent hPSC lines. Isogenic sets were differentiated to hPSC-CMs for high-throughput, non-subjective molecular and functional assessment using 12 approaches in 2D monolayers and/or 3D engineered heart tissues. Although immature, edited hPSC-CMs exhibited the main hallmarks of HCM (hypertrophy, multi-nucleation, hypertrophic marker expression, sarcomeric disarray). Functional evaluation supported the energy depletion model due to higher metabolic respiration activity, accompanied by abnormalities in calcium handling, arrhythmias, and contraction force. Partial phenotypic rescue was achieved with ranolazine but not omecamtiv mecarbil, while RNAseq highlighted potentially novel molecular targets.Conclusion: Our holistic and comprehensive approach showed that energy depletion affected core cardiomyocyte functionality. The engineered R453C-βMHC-mutation triggered compensatory responses in hPSC-CMs, causing increased ATP production and αMHC to energy-efficient βMHC switching. We showed that pharmacological rescue of arrhythmias was possible, while MHY7: MYH6 and mutant: wild-type MYH7 ratios may be diagnostic, and previously undescribed lncRNAs and gene modifiers are suggestive of new mechanisms.

U2 - 10.1093/eurheartj/ehy249

DO - 10.1093/eurheartj/ehy249

M3 - SCORING: Journal article

VL - 39

SP - 3879

EP - 3892

JO - EUR HEART J

JF - EUR HEART J

SN - 0195-668X

IS - 43

ER -