Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling...

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Bibliographic Details
Published in:PloS one 2016-01, Vol.11 (1), p.e0146697-e0146697
Main Authors: Cashman, Timothy J, Josowitz, Rebecca, Johnson, Bryce V, Gelb, Bruce D, Costa, Kevin D
Format: Article
Language:English
Subjects:
Aberration
Atrial Natriuretic Factor - genetics
Atrial Natriuretic Factor - metabolism
Atrial natriuretic peptide
Biomedical materials
Cardiac arrhythmia
Cardiomyocytes
Cardiomyopathy
Cardiomyopathy, Hypertrophic - genetics
Cardiomyopathy, Hypertrophic - physiopathology
Cell culture
Cell cycle
Cell Differentiation
Cells, Cultured
Childrens health
Chlorofluorocarbons
Contraction
Coronary artery disease
Development and progression
Equipment and supplies
Gene expression
Genetic disorders
Health aspects
Heart
Heart diseases
Human subjects
Humans
Hypertrophic cardiomyopathy
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Kinases
MAP kinase
Medicine
Methods
Mutation
Myocardial Contraction
Myocytes
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Patients
Pluripotency
Principal components analysis
Proto-Oncogene Proteins B-raf - genetics
Rodents
Signaling
Stem cells
Stiffness
Substrates
Three dimensional models
Tissue Engineering
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Summary:Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death that often goes undetected in the general population. HCM is also prevalent in patients with cardio-facio-cutaneous syndrome (CFCS), which is a genetic disorder characterized by aberrant signaling in the RAS/MAPK signaling cascade. Understanding the mechanisms of HCM development in such RASopathies may lead to novel therapeutic strategies, but relevant experimental models of the human condition are lacking. Therefore, the objective of this study was to develop the first 3D human engineered cardiac tissue (hECT) model of HCM. The hECTs were created using human cardiomyocytes obtained by directed differentiation of induced pluripotent stem cells derived from a patient with CFCS due to an activating BRAF mutation. The mutant myocytes were directly conjugated at a 3:1 ratio with a stromal cell population to create a tissue of defined composition. Compared to healthy patient control hECTs, BRAF-hECTs displayed a hypertrophic phenotype by culture day 6, with significantly increased tissue size, twitch force, and atrial natriuretic peptide (ANP) gene expression. Twitch characteristics reflected increased contraction and relaxation rates and shorter twitch duration in BRAF-hECTs, which also had a significantly higher maximum capture rate and lower excitation threshold during electrical pacing, consistent with a more arrhythmogenic substrate. By culture day 11, twitch force was no longer different between BRAF and wild-type hECTs, revealing a temporal aspect of disease modeling with tissue engineering. Principal component analysis identified diastolic force as a key factor that changed from day 6 to day 11, supported by a higher passive stiffness in day 11 BRAF-hECTs. In summary, human engineered cardiac tissues created from BRAF mutant cells recapitulated, for the first time, key aspects of the HCM phenotype, offering a new in vitro model for studying intrinsic mechanisms and screening new therapeutic approaches for this lethal form of heart disease.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0146697