Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 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

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 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.

Citation

Smith, J. G., Owen, T., Bhagwan, J. R., Mosqueira, D., Scott, E., Mannhardt, I., …Denning, C. (2018). Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits. Stem Cell Reports, 11(5), 1226-1243. https://doi.org/10.1016/j.stemcr.2018.10.006

• Journal Article Type: Article
• Acceptance Date: Oct 5, 2018
• Online Publication Date: Nov 1, 2018
• Publication Date: Nov 13, 2018
• Deposit Date: Oct 8, 2018
• Publicly Available Date: Nov 2, 2018
• Journal: Stem Cell Reports
• Electronic ISSN: 2213-6711
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 5
• Pages: 1226-1243
• DOI: https://doi.org/10.1016/j.stemcr.2018.10.006
• Public URL: https://nottingham-repository.worktribe.com/output/1151121
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2213671118304296
• Additional Information: This article is maintained by: Elsevier; Article Title: Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits; Journal Title: Stem Cell Reports; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.stemcr.2018.10.006; Content Type: article; Copyright: © 2018 The Author(s).