Engineering Brain Organoids to Probe Impaired Neurogenesis Induced by Cadmium

Brain organoids derived from human induced pluripotent stem cells (hiPSCs) are three-dimensional in vitro models with near-physiological cellular composition and structural organization, which is representative of the developing human brain. They provide an ideal experimental system for the investigation of brain development and diseases. Prenatal exposure to the heavy metal cadmium (Cd) poses a serious health threat, particularly to the developing brain due to a long biological half-life of Cd in vivo. Although it is known that prolonged exposure to Cd will cause toxic effects because of its low rate of excretion from the body, the underlying mechanisms of Cd neurotoxicity remain unclear. Herein, we proposed a simple approach to engineer brain organoids on an array chip with octagon-shaped micropillars and explored neural dysfunctions of brain organoids under Cd exposure. hiPSC-derived brain organoids with millimeter-size recapitulated spatial and temporal patterning events in the early developing brain, including gene expression programs and three-dimensional organization. With Cd exposure, brain organoids displayed induced cell apoptosis, skewed neural differentiation, and varied brain regionalization, indi- cating the presence of impaired neurogenesis in the human fetal brain. This work provides a simple manner to generate brain organoids efficiently and a powerful platform for the investigation of abnormal neurogenesis induced by many different toxic factors in vitro.