Scientific publications
Melt electrowritten 3D human cardiac engineered tissues reproduce the enhanced sensitivity of fibrotic patients to doxorubicin
A Sanchez-Bueno, A Ullate-Agote, P Montero-Calle, J Valdes-Fernandez, E Larequi, I Anaut-Lusar, P San Martin-Uriz, P Aguirre-Ruiz, A De La Fuente, L Sanchez-Lorenzo, M Garcia De Yebenes, O Iglesias-Garcia, J J Gavira, F Prosper, M Mazo Vega
Abstract
Introduction
Cardiotoxicity is a serious and frequent side effect of anthracycline cancer therapy, prompting the cardio-oncologic follow up of patients. However, mechanisms are poorly understood. Moreover, cardiac patients demonstrate an enhance frequency and severity of cardiotoxic events.
Purpose
In this work we use melt electrowriting (MEW) to generate human induced pluripotent stem cell (hiPSC)-based 3D cardiac tissues to explore this.
Methods
3D scaffolds were printed using MEW in medical grade poly-caprolactone. Human iPSCs were differentiated to cardiomyocytes and cardiac fibroblasts using chemically-defined methods, embedded in a fibrinogen precursor and polymerised around the 3D scaffold with thrombin. 3D engineered myocardia were maintaned in vitro an analysed.
Results
Using a combination of 80% hiPSC-cardiomyocytes and 20% hiPSC-cardiac fibroblasts, we demonstrate that treating MEW-based tissues with clinically-relevant concentrations of the anthracycline doxorubicin recapitulates the main features of cardiac toxicity, including diminished viability and functionality, and severe sarcomeric disarrangement. Moreover, we use TGFβ-treatment to induce a tissue fibrosis, akin to the response in cardiac-diseased patients. Upon treatment with 250 nM doxorubicin, fibrotic MEW-myocardial tissues show significantly worst performance, with decreased viability and functionality as compared with non-TGFβ-treated engineered tissues. Finally, we apply bulk RNAseq, showing how both models faithfully recapitulate the main features of natural human myocardium.
Conclusions
In summary, we demonstrate that our all-human MEW-based 3D engineered cardiac tissue are able to recapitulate the enhanced clinical cardiotoxicity of cardiac patients in response to anthracycline therapy. Our system is thus posed as an optimal candidate for prophylactic-drug discovery and mechanism deciphering.
CITA DEL ARTÍCULO European Heart Journal Supplements, Volume 27, Issue Supplement_6, August 2025, suaf083.216, https://doi.org/10.1093/eurheartjsupp/suaf083.216
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