Human brain organoid-on-a-chip to model prenatal nicotine exposure.

Nicotine has been recognized to trigger various neuronal disabilities in the fetal brain and long-lasting behavioral deficits in offspring. However, further understanding of fetal brain development under nicotine exposure is challenging due to the limitations of existing animal models. Here, we create a new brain organoid-on-a-chip system derived from human induced pluripotent stem cells (hiPSCs) that allows us to model neurodevelopmental disorders under prenatal nicotine exposure (PNE) at early stages. The brain organoid-on-a-chip system facilitates 3D culture, in situ neural differentiation, and self-organization of brain organoids under continuous perfused cultures in a controlled manner. The generated brain organoids displayed well-defined neural differentiation, regionalization, and cortical organization, which recapitulates the key features of the early stages of human brain development. The brain organoids exposed to nicotine exhibited premature neuronal differentiation with enhanced expression of the neuron marker TUJ1. Brain regionalization and cortical development were disrupted in the nicotine-treated organoids identified by the expressions of forebrain (PAX6 and FOXG1), hindbrain (PAX2 and KROX20) and cortical neural layer (preplate TBR1 and deep-layer CTIP2) markers. Moreover, the neurite outgrowth showed abnormal neuronal differentiation and migration in nicotine-treated brain organoids. These results suggest that nicotine exposure elicits impaired neurogenesis in early fetal brain development during gestation. The established brain organoid-on-a-chip system provides a promising platform to model neurodevelopmental disorders under environmental exposure, which can be extended for applications in brain disease studies and drug testing.