Sex-Specific Changes in Brain Organoids from Acute Simulated Galactic Cosmic Radiation are Rescued by Targeted ECM Pathway Stimulation

Abstract

As deep-space missions become increasingly feasible, understanding the health risks posed by galactic cosmic rays (GCR) is critical. This study investigates the effects of a simplified 5-ion GCR simulation (simGCRsim) on human brain organoids derived from 12 human induced pluripotent stem cell (hiPSC) lines. Male organoids exhibit increased vulnerability, characterized by reduced SOX2-positive neural progenitor populations, downregulation of outer kinetochore genes including components of the NDC80 complex, centromere loss, and elevated nuclear p53 accumulation. Female organoids also exhibit radiation-induced neuronal damage but show comparatively lower levels of centromere disruption and p53 activation than males. To counteract these effects, an optogenetically controlled FGF2 signaling system is applied, leveraging plant-derived light-sensitive domains. Activation of this system enhances extracellular matrix (ECM) expression, resulting in significant neuroprotection against simGCRsim-induced damage. Furthermore, exogenous ECM supplementation alone effectively mitigated radiation-induced neural injury in both male and female brain organoids. These findings highlight the central role of ECM in neuroprotection under cosmic radiation exposure and suggest a potential strategy for safeguarding astronaut brain health during long-duration spaceflight.