Using 3D Cardiac Models derived from hPSCs for Cardiac Toxicity Studies during Heart Development

Tiago Alexandre Correia Nunes

Key information

Authors:

Tiago Alexandre Correia Nunes (Tiago Alexandre Correia Nunes)

Supervisors:

Maria Margarida Fonseca Rodrigues Diogo (Maria Margarida Fonseca Rodrigues Diogo); Mariana da Mota Veiga de Araújo Branco (Mariana da Mota Veiga de Araújo Branco)

Published in

11/29/2022

Abstract

The detection of cardiotoxic effects during drug development is a leading cause of attrition. Developmental cardiotoxicity assessment is particularly limited by the inability of pregnant women to participate in clinical trials, emphasizing the need to develop pre-clinical platforms able to accurately predict the drug’s fetal safety profile. The use of human pluripotent stem cells (hPSCs) for engineering in vitro heart models is a promising solution. The majority of hPSC-based cardiotoxicity studies has been performed using 2D cardiac models which do not recapitulate the complex microenvironment of the heart. Furthermore, there is a lack of reliable studies focused on assessing functional and structural toxicity during the early stages of heart development. In this work, a 3D cardiac model was used to study the developmental cardiotoxicity of nine pharmaceutical compounds. The drug-induced impacts were assessed at the level of (i) mesoderm and endoderm progenitor population commitment, and (ii) cardiac cells specification into cardiomyocytes, using different drug exposure strategies. We observed that the timing of drug exposure had impact on the level of toxicity, and that early drug exposure could result in an imbalance of mesoderm and endoderm progenitor populations and a disruption of their spatial organization. The 3D cardiac model used in this study allowed to detect defects at the level of cavity formation, which was particularly relevant in the case of thalidomide. Thus, the presented platform has the potential to detect drug-induced cardiotoxicity during development at both structural and functional levels, and to help clarifying the mechanisms behind the detected toxicity.