Characterization of stem cell-derived human dopaminergic neuron subtypes

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Canada is a leader in research on movement disorders, especially Parkinson's Disease (PD). As the second most common neurodegenerative condition, PD is responsible for substantial economic, societal, and personal burden. Efforts to uncover effective approaches to treat PD patients are a high priority, and research to help us better understand how neurons are lost in the brains of PD patients is essential to reach therapeutic goals. Dopaminergic (DA) neurons have long been known as the cell type affected in PD; recent findings have revealed that this cell population is more complex than we previously thought and there are actually more than six subtypes of DA neurons. Some of these subtypes are more susceptible than others in PD. This is an important discovery with clinical implications, but our current understanding of DA neuron subtypes is limited.Incredibly, neuroscience researchers are now able to generate human DA neurons in the lab from easy to generate stem cells derived from human patients, termed induced pluripotent stem cells (iPSCs). iPSC-derived DA neurons have served as powerful tools to model the onset and progression of PD, and to uncover potential therapeutic compounds in large-scale screening experiments. There are substantial limitations, however, to our current protocols for iPSC-DA neuron generation. These include inefficient differentiation (typically, only ~30% of neurons generated are of DA identity) and a lack of knowledge as to which DA neuron subtypes are produced. In this proposal we will use high throughput compound screening and imaging methods to improve the efficiency of iPSC-derived DA neuron production and permit reliable stratification of the subgroups produced. Our goal is to optimize existing protocols so researchers can directly produce individual subgroups of DA neurons from iPSCs. This proposal will harness the complementary expertise of: 1) the Julian and Vocadlo labs at Simon Fraser University, experts in neuroscience, biological regulation of cell fate determination and high-throughput analysis; and 2) Dr. Erin Knock and her Neuroscience team at STEMCELL Technologies, an internationally renowned Vancouver-based company with long established expertise in optimization of iPSC neuronal differentiation strategies. Our team is uniquely poised to conduct this work that we anticipate will substantially impact the PD and movement disorder research communities.