Biology subjects

Baatout, S.

Publications and source records attributed to Baatout, S..

3 recordsLinked to original sources

bioRxiv2026

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

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.

bioengineering↗

bioRxiv2024

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in forebrain organoids

AbstractPrenatal radiation-induced DNA damage poses a significant threat to normal brain development, resulting in microcephaly which primarily affects the cerebral cortex. It is unclear which molecular mechanisms are at the basis of this defect in humans as the few mechanistic studies performed so far were done in animals. Here, we leveraged human embryonic stem cell- derived forebrain organoids as a model for human corticogenesis. Organoids were X-irradiated with a moderate and a high dose at different time points, representing very early and mid corticogenesis. Irradiation caused a dose- and developmental-timing-dependent reduction in organoid size, which was more prominent in developmentally younger organoids. This coincided with a dose-dependent canonical p53-DREAM-dependent DNA damage response (DDR), consisting of cell cycle arrest, DNA repair and apoptosis. The DDR was delayed and less pronounced in the older organoids. Besides the DDR, we observed radiation-induced premature differentiation of neural progenitors and changes in metabolism. Importantly, our transcriptomic analysis furthermore demonstrated a concerted p53-E2F4-dependent repression of primary microcephaly genes. We found that this was a human-specific feature, as it was not observed in mouse embryonic brains or primary mouse neural progenitor cells. Thus, human forebrain organoids are an excellent model to investigate prenatal DNA damage-induced microcephaly and to uncover potentially targetable human-specific pathways.

developmental biology↗

bioRxiv2020

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

p53 regulates the cellular DNA damage response (DDR). Hyperactivation of p53 during embryonic development, however, can lead to a range of developmental defects including microcephaly. Here, we induce microcephaly by acute irradiation of mouse fetuses at the onset of neurogenesis. Besides a classical DDR culminating in massive apoptosis, we observe ectopic neurons in the subventricular zone in the brains of irradiated mice, indicative of premature neuronal differentiation. A transcriptomic study indicates that p53 activates both DDR genes and differentiation-associated genes. In line with this, mice with a targeted inactivation of Trp53 in the dorsal forebrain, do not show this ectopic phenotype and partially restore brain size after irradiation. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process resembling the radiation-induced proneural-mesenchymal transition in glioma and glioma stem-like cells. Our results demonstrate a critical role for p53 beyond the DDR as a regulator of neural progenitor cell fate in response to DNA damage.

neuroscience↗