Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits
| Autor: | 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 |
|---|---|
| Přispěvatelé: | British Heart Foundation |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
MECHANISM
Heart Defects Congenital Induced Pluripotent Stem Cells CHILDREN MOUSE arrhythmia CARDIOMYOCYTES Article Cell & Tissue Engineering contractile function Humans Myocytes Cardiac ABERRANT CA2+ RELEASE Calcium Signaling lcsh:QH301-705.5 health care economics and organizations ENGINEERED HEART-TISSUE GENE-EXPRESSION Gene Editing lcsh:R5-920 Science & Technology Tissue Engineering Arrhythmias Cardiac Cell Biology Cardiomyopathy Hypertrophic DILATED CARDIOMYOPATHY Myocardial Contraction Actins ALPHA-CARDIAC ACTIN lcsh:Biology (General) Mutation Calcium CRISPR-Cas Systems lcsh:Medicine (General) hypertrophy Life Sciences & Biomedicine PLURIPOTENT STEM-CELLS cardiomyopathy |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 11, Iss 5, Pp 1226-1243 (2018) |
| ISSN: | 2213-6711 |
| Popis: | Summary 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. Highlights • Arrhythmia was a hallmark phenotype in E99K hiPSC-CMs, provoked by altered [Ca2+] • Monoallelic expression of E99K cardiac actin affects only half the cell population • Severe phenotypes in father's E99K hiPSC-CMs suggest influence of age & epigenetics • Mechanistic insight facilitated drug rescue with combined dantroline/ranolazine In this article Smith, Denning and colleagues show that the E99K-ACTC1 cardiac actin mutation is a central cause of HCM, but the three-way interaction between the primary genetic lesion, background genetics, and donor patient age may influence the pathogenic phenotype. Pharmacological rescue experiments demonstrated dual dantroline/ranolazine to be an effective treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|