Personalized Human Astrocyte‐Derived Region‐Specific Forebrain Organoids Recapitulate Endogenous Pathological Features of Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is a highly heterogeneous neurodevelopmental malformation, the underlying mechanisms of which remain largely elusive. In this study, personalized dorsal and ventral forebrain organoids (DFOs/VFOs) are generated derived from brain astrocytes of patients with FCD type II (FCD II). The pathological features of dysmorphic neurons, balloon cells, and astrogliosis are successfully replicated in patient-derived DFOs, but not in VFOs. It is noteworthy that cardiomyocyte-like cells correlated with dysmorphic neurons are generated through the high activation of BMP and WNT signaling in some of the FCD-organoids and patient cortical tissues. Moreover, functional assessments demonstrated the occurrence of epileptiform burst firing and propagative self-assembling neuronal hyperactivity in both FCD-DFOs and VFOs. Additionally, the heterotopic cardiomyocyte-organoids demonstrated the capacity for cardiomyocyte contraction and rhythmic firing. The presence of these cardiomyocytes contributes to the hyperactivity of neural networks in cardioids-DFOs assembly. In conclusion, the personalized region-specific forebrain organoids derived from FCD patient astrocytes effectively recapitulate heterogeneous pathological features, offering a valuable platform for the development of precise therapeutic strategies.