Engineered Heart Tissues for Cardiovascular Disease Modeling

Beatriz Assunção Gamelas

Key information

Authors:

Beatriz Assunção Gamelas (Beatriz Assunção Gamelas)

Supervisors:

Marcelo Catarino Ribeiro; Tiago Paulo Gonçalves Pinheiro Fernandes (Tiago Paulo Gonçalves Fernandes)

Published in

01/25/2021

Abstract

Cardiovascular diseases are the leading cause of disability and death worldwide, representing a major economic burden in healthcare systems. Heart failure (HF) and hypertrophic cardiomyopathy (HCM) are amongst the most severe of these conditions and currently there is no effective cure for them. Although several animal or 2D models have been developed and used in preclinical drug trials, they lack accuracy when it comes to mimic the native 3D cardiac microenvironment, leading to failure in predicting disease phenotype and drug toxicity. The urgent demand for new 3D in vitro models, coupled with human stem cell biology breakthroughs, have allowed the successful generation of engineered heart tissues (EHTs) and advanced the fields of disease modeling, drug development and regenerative medicine. Particularly, Human Induced Pluripotent Stem Cells (hiPSCs), when differentiated into cardiomyocytes (hiPSC-CMs), are the best stem cell type to recapitulate cardiomyocyte physiology. In this project, a fibrin-based platform was used to simulate HCM by generating EHTs with isogenic hiPSC lines that only differed in a single nucleotide mutation in the MYBPC3 gene (the most common cause of HCM, this gene encodes for myosin binding protein C, crucial for sarcomere organisation and cardiac muscle contraction). Furthermore, the platform was used to simulate HF after long-term exposure of tissues composed by hiPSC-CMs to norepinephrine. The platform was able to successfully replicate key aspects of both diseases, particularly contractile dysfunction that is also observed in human patients, which may help to find their pathomechanisms and new and efficient therapeutics.