Unlocking the secrets of human brain development using stem cells

During brain development, neural stem cells follow carefully timed programs that determine when they divide and which types of neurons they produce. We study how these temporal programs are regulated, with a focus on the generation of upper-layer neurons that support higher cognitive functions. By using stem-cell-based models and genetic approaches, including working with CCHMC clinicians to study patient mutations, we aim to understand how disruptions in these processes contribute to neurodevelopmental/neuropsychiatric disorders including autism.

Nearly half of children who need life-saving heart surgery later develop challenges with learning, memory, or behavior. We don’t yet know whether these problems are mainly caused by the medical environment or by genetics. Neural crest cells are a unique population that contributes to both the developing heart and the nervous system. Disruptions in their development can lead to congenital heart defects, such as those seen in Noonan syndrome, DiGeorge syndrome, and hypoplastic left heart syndrome. We are developing stem-cell-based protocols to generate cardiac neural crest cells in vitro, allowing us to investigate how these cells build the outflow tract of the heart and how their dysfunction may also impact brain development.

The olfactory system is often among the first to show signs of decline in neurodegenerative diseases such as Alzheimer’s and Down syndrome. To study this early vulnerability, we are creating organoid models of both the olfactory epithelium, which detects odors, and the olfactory bulb, which processes them in the brain. These stem-cell-derived systems provide a platform to investigate the cellular and molecular changes that underlie sensory dysfunction and to identify potential points for intervention in early neurodegeneration.