Engineering in vitro brainstem models with guidance from development
The brainstem and the spinal cord are responsible for control of respiration, heart rate, as well as sensory and motor function. Though critical for human life, these tissues are highly vulnerable to injury and disease. Determining how the brainstem and spinal cord develop and engineering in vitro models of these tissues can enable cell replacement strategies as well as provide a testbed to study genetic mutation and disease. My research has led to the development of in vitro protocols to differentiate stem cells into V2a interneurons, an excitatory interneuron found in the spinal cord and brainstem, for applications in spinal cord injury. This work grew into the generation of 3D organoid models which contain many cell types represented in the developing brainstem. To ultimately improve in vitro differentiation, I have currently been studying a neural lineage marked by the Atoh1 transcription factor in the developing mouse that gives rise to over 40 different types of neurons in the cerebellum and brainstem. Utilizing multi-omic strategies, I have identified key aspects of Atoh1-lineage development including the spatial priming of cell-fate at the progenitor stage, the critical role of Atoh1 function during migration, and identification of novel markers of mature Atoh1-lineage neurons. Future work will capitalize on findings from the developing mouse to guide the design of Atoh1-lineage in vitro models. These in vitro models can be used to further elucidate developmental pathways as well as generate translational testbeds and therapeutics for the compromised brainstem.
Dr. Jessica Butts completed her Bachelor of Science Degree in Biomedical Engineering at Washington University in St. Louis where she worked with Dr. Shelly Sakiyama-Elbert to develop the first directed differentiation protocol of V2a interneurons from mouse embryonic stem cells. Jessica then completed her doctoral work with Todd McDevitt at the Gladstone Institutes receiving a PhD in Bioengineering from the University of California – San Francisco and Berkeley. Her work focused on deriving caudal interneurons from human pluripotent stem cells. Jessica is now a HHMI postdoctoral fellow with Dr. Huda Zoghbi at Baylor College of Medicine researching neuronal fate decisions in the developing hindbrain. This work was funded by an F32 NRSA from the NINDS. Her long-term research goals are to utilize tissue engineering strategies and multi-omic approaches to develop mouse and human stem cell-derived brainstem organoid models mimicking native neural development.