PhD Defense | Emil Rehnberg | Development of 3D models to study cardiac aging in Space

Development of 3D models to study cardiac aging in Space

Human space exploration beyond low Earth orbit poses a profound risk to astronaut health, specifically by inducing an accelerated aging-like effect on the cardiovascular system. Spaceflight stressors like microgravity and cosmic radiation drive structural remodeling, altered electrophysiology, and functional decline. However, mechanistic research and countermeasure development are hindered by the scarcity of human flight samples and the physiological limitations of animal and simple 2D cell models. To bridge this gap, this thesis developed an advanced, human-relevant 3D in vitro platform.

First, we engineered reCardioids, a robust, highly reproducible human induced pluripotent stem cell-derived heart organoid model. By dissociating and reaggregating self-organizing cardioids, we eliminated functional variability while achieving enhanced cardiomyocyte maturation. The platform's predictive utility was validated by modeling doxorubicin-induced cardiotoxicity and clinical γ-ray radiotherapy exposure. Exposure to radiation revealed dose-dependent sluggish contraction dynamics alongside a transcriptomic progression from acute DNA damage to vascular impairment and hypertrophic remodeling.

To elevate physiological complexity, reCardioids were integrated with a perfusable vascular bed to create a Heart Organoid-on-Chip (HOoC) allowing for convective mass transport. When exposed to a galactic cosmic ray simulator combined with simulated microgravity, the HOoCs successfully captured a stress-induced cardiac aging state. While contractile impairment worsened dose-dependently and was most pronounced under microgravity alone, combining simulated microgravity with a 50 mGy radiation dose attenuated this severe contractile slowing, resulting in no significant differences compared to the 50 mGy exposure under normal gravity. However, transcriptomic analysis revealed this antagonistic interaction was not a rescue effect, but rather a profound structural and electromechanical crisis. Over 72 hours, transcriptomic profiling suggested the tissue transitioned from acute inflammation and pro-arrhythmic signaling to a sustained maladaptive state, characterized by gene expression signatures indicative of a senescence-associated secretory phenotype, vascular regression, and severe excitation-contraction uncoupling.

Ultimately, this thesis establishes a robust suite of 3D in vitro models, providing crucial tools for investigating fundamental mechanisms and developing countermeasures against both spaceflight-induced cardiovascular deconditioning and terrestrial age-related heart diseases, in the future.

Promoters:

Prof. Sarah Baatout, Ghent University

Prof. Lorenzo Moroni, Maastricht University (co-promoter)

SCK CEN mentors:

Dr. Eng. Kevin Tabury

Dr. Bjorn Baselet