Ethan Katz
Modeling Abnormal Brain Development in Tuberous Sclerosis with a Structurally Reproducible Bioprinting-initiated Human Cerebral Organoid System
Tuberous Sclerosis (TS) is a devastating developmental disease marked by tumors growing throughout the body. The specific impacts on the brain highlight TS as a profound neurodevelopmental and cortical malformation syndrome, resulting in the formation of abnormal brain cells and structures. These changes in how the brain forms alter how the brain functions, leading to epilepsy, autism spectrum disorder, and cognitive deficits.
TS is caused by loss of function mutations in the TSC1 or TSC2 genes, whose protein products are responsible for inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway. This crucial master regulator of protein production and cell metabolism relies on a carefully fine-tuned system of control鈥攁 system that, in the case of TS, has had its brakes cut. Today鈥檚 treatment of TS is terribly limited and what is available is far from what will really benefit patients. Therefore, studying how the disease progresses from its earliest stage is crucial to understand how these brain malformations arise and to identify effective therapeutic approaches. Unfortunately, current models of the developing human brain are inadequate in their structural reproduction to investigate the unique architectural changes seen in this cortical malformation syndrome.
The goal of my project is to establish a new 鈥渙rganoid鈥� model of early brain development derived from human induced pluripotent stem cells (hiPSCs), specifically one that reproduces the brain鈥檚 radial organization around a central lumen. Using precision 3D-bioprinting to produce extracellular matrix (ECM) islands that mimic embryonic size constraints, we generate a self-folded structurally sound neural tube model. These engineered neural tubes are used as seed tissues from which to grow cerebral organoids鈥攎ini reconstructions of part of the developing brain鈥攖hat closely recapitulate the brain鈥檚 natural organization. We will use these structurally reproducible cerebral organoids to identify the first visible deviations in TS brain development and examine the mechanisms driving these critical alterations. Further work in this model holds the potential to expand our understanding of TS pathogenesis and to screen in high throughput for functional drug interventions. This widely applicable method will be an incredible advance for the TS field, and since the disease we model depends only on the genetics of the input hiPSCs, unique patient-specific mutations could be assessed to further deepen our understanding of early pathogenic cellular and structural aberrations across a broad range of neurodevelopmental conditions.