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Updated: Dec 20, 2025
Sarcomere Shortening of Pluripotent Stem Cell-Derived Cardiomyocytes using Fluorescent-Tagged Sarcomere Proteins.
Published on: March 3, 2021
INDUCED PLURIPOTENT STEM CELLS FOR MODELLING ENERGETIC ALTERATIONS IN HYPERTROPHIC CARDIOMYOPATHY
Chrishan J A Ramachandra1,2, K P Myu Mai Ja1, Ying-Hsi Lin1,2
1National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
Insights
Hypertrophic cardiomyopathy (HCM) research uses humanized models. Induced pluripotent stem cell-derived cardiomyocytes from HCM patients reveal altered cellular energetics, crucial for understanding disease mechanisms.
Area of Science:
- Cardiovascular Genetics
- Stem Cell Biology
- Molecular Cardiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by ventricular wall thickening and myofiber disarray.
- Primary sarcomeric gene mutations in HCM lead to complex secondary phenotypes, including cellular hypertrophy and energy deficiency.
- Existing animal models have limitations due to species variation and the scarcity of human myocardial tissue.
Purpose of the Study:
- To review humanized models for studying Hypertrophic Cardiomyopathy (HCM) pathogenesis.
- To emphasize the investigation of altered energetics in HCM using induced pluripotent stem cell (iPSC)-derived cardiomyocytes.
- To assess the recapitulation of pathophysiological features, particularly energy deficiency, in iPSC-based HCM models.
Main Methods:
- Generation of human cardiomyocytes (CMs) from patients with HCM using induced pluripotent stem cells (iPSCs).
- Phenotypic characterization of HCM-iPSC models.
- Analysis of cellular energetics and energy metabolism in patient-derived iPSC-CMs.
Main Results:
- HCM-iPSC models exhibit key phenotypic traits of the disease, including cardiomyocyte hypertrophy.
- These models are instrumental in investigating the molecular mechanisms linking sarcomeric defects to secondary phenotypes.
- Focus on altered energetics in HCM-iPSC models provides insights into a critical contributor to disease pathogenesis.
Conclusions:
- Humanized models, specifically iPSC-derived CMs, are valuable tools for studying Hypertrophic Cardiomyopathy (HCM).
- These models allow for the investigation of disease mechanisms not fully understood through traditional methods.
- Altered cellular energetics is a significant aspect of HCM pathogenesis that can be effectively studied in iPSC-derived models.
Abstract:
Hypertrophic cardiomyopathy (HCM) is one of the most commonly inherited cardiac disorders that manifests with increased ventricular wall thickening, cardiomyocyte hypertrophy, disarrayed myofibers and interstitial fibrosis. The major pathophysiological features include, diastolic dysfunction, obstruction of the left ventricular outflow tract and cardiac arrhythmias. Mutations in genes that encode mostly for sarcomeric proteins have been associated with HCM but, despite the abundant research conducted to decipher the molecular mechanisms underlying the disease, it remains unclear as to how a primary defect in the sarcomere could lead to secondary phenotypes such as cellular hypertrophy. Mounting evidence suggests energy deficiency could be an important contributor of disease pathogenesis as well. Various animal models of HCM have been generated for gaining deeper insight into disease pathogenesis, however species variation between animals and humans, as well as the limited availability of human myocardial samples, has encouraged researchers to seek alternative 'humanized' models. Using induced pluripotent stem cells (iPSCs), human cardiomyocytes (CMs) have been generated from patients with HCM for investigating disease mechanisms. While these HCM-iPSC models demonstrate most of the phenotypic traits, it is important to ascertain if they recapitulate all pathophysiological features, especially that of energy deficiency. In this review we discuss the currently established HCM-iPSC models with emphasis on altered energetics.
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