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Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy
Published on: March 1, 2016
Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of
Timothy J Cashman1, Rebecca Josowitz2, Bryce V Johnson1
1The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York City, New York, United States of America.
Insights
Researchers developed a novel 3D human engineered cardiac tissue (hECT) model to study hypertrophic cardiomyopathy (HCM) in cardio-facio-cutaneous syndrome (CFCS). This model recapitulates key HCM features, offering new avenues for therapeutic development.
Area of Science:
- Cardiovascular Biology
- Genetic Disorders
- Biomedical Engineering
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary cause of sudden cardiac death, often undiagnosed.
- HCM is frequently observed in cardio-facio-cutaneous syndrome (CFCS), a genetic disorder linked to RAS/MAPK pathway dysregulation.
- Existing experimental models do not fully represent human HCM in RASopathies.
Purpose of the Study:
- To create the first 3D human engineered cardiac tissue (hECT) model for studying HCM.
- To investigate HCM mechanisms in the context of CFCS using patient-derived cells.
- To establish a novel in vitro platform for therapeutic screening.
Main Methods:
- Directed differentiation of induced pluripotent stem cells from a CFCS patient with a BRAF mutation to generate cardiomyocytes.
- Co-culturing mutant cardiomyocytes with stromal cells at a 3:1 ratio to form hECTs.
- Assessing tissue size, contractility, electrical properties, and gene expression over time.
Main Results:
- BRAF-hECTs exhibited a hypertrophic phenotype by day 6, with increased size, twitch force, and ANP expression compared to controls.
- Altered twitch dynamics, higher maximum capture rate, and lower excitation threshold indicated arrhythmogenic potential.
- Temporal changes in diastolic force and passive stiffness were observed by day 11, highlighting disease progression dynamics.
Conclusions:
- Human engineered cardiac tissues from BRAF mutant cells successfully model key aspects of HCM.
- This novel hECT model provides a platform for understanding HCM pathogenesis in RASopathies.
- The model can be utilized for screening potential therapeutic strategies for HCM.
Abstract:
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.
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