ReCardioids: a robust human heart organoid platform to model doxorubicin- and radiotherapy-induced cardiotoxicity

Rehnberg, E.; Baselet, B.; Etlioglu, E.; Janssen, Z.; Cools, B.; Van Rompay, C.; Vermeesen, R.; Moroni, L.; Baatout, S.; Tabury, K.

doi:10.64898/2026.05.29.728705

bioRxiv · 10.64898/2026.05.29.728705

ReCardioids: a robust human heart organoid platform to model doxorubicin- and radiotherapy-induced cardiotoxicity

Rehnberg, E.·Baselet, B.·Etlioglu, E.·Janssen, Z.·Cools, B.·Van Rompay, C.·Vermeesen, R.·Moroni, L.·Baatout, S.·Tabury, K.

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Abstract

As global cancer incidence rises, so does the population of cancer survivors, making long-term and post-treatment quality of life a central clinical concern. Despite modern improvements in treatment, cardiotoxic side effects caused by anthracycline agents and thoracic radiotherapy remain a major clinical challenge. Human iPSC-derived heart organoids offer a promising alternative to animal and 2D in vitro models, but their utility is limited by inter-organoid variability. To address this, we developed reCardioids, a robust heart organoid model generated by dissociation and reaggregation of self-assembling cardioids. Through single-cell transcriptomics, we demonstrated that reCardiods maintain cellular diversity while also exhibiting a more mature cardiomyocyte phenotype compared to non-dissociated cardioids. To validate their utility as a preclinical in vitro model, we evaluated their response after exposure to doxorubicin and clinically relevant doses of {gamma}-radiation. reCardioids successfully modeled doxorubicin-induced cytotoxicity, metabolic decline and altered contractile dynamics. Bulk RNA sequencing following radiation exposure revealed a temporal trajectory of injury, progressing from acute DNA damage through vascular stunting, metabolic dysfunction and eventually compensatory pathological hypertrophic remodeling.

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Rehnberg, E., Baselet, B., Etlioglu, E., Janssen, Z., Cools, B., Van Rompay, C., Vermeesen, R., Moroni, L., Baatout, S., Tabury, K.. 2026-06-02. ReCardioids: a robust human heart organoid platform to model doxorubicin- and radiotherapy-induced cardiotoxicity. https://doi.org/10.64898/2026.05.29.728705

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