Genetic and physiological comparison of native human sensory neurons and induced pluripotent stem cells differentiated to sensory neurons

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Project Summary Sensory neurons in the dorsal root ganglia are the primary source of nociceptive (pain) signaling and are susceptible to genetic and functional alterations as a result of injury or disease, thus resulting in chronic pain. Understanding the mechanisms underlying these alterations and gaining the capability to reverse them is a major objective of pain research, and is expected to produce medical advances that reduce patient suffering. Most of the existing information on these neurons is derived from animal models, which has unfortunately led to few clinical successes. Recently, increased access and use of human dorsal root ganglia as well as sensory neurons derived from human induced pluripotent stem cells have positioned the field to improve mechanistic understanding in human cells and advance translation to human drug discovery. However, research on native human sensory neurons and differentiated sensory neurons from human stem cells have progressed on independent trajectories, and therefore have not been adequately compared, leaving open the likely possibility that differentiated stem cells exhibit differences from native sensory neurons that are critical for understanding injury and disease progression toward chronic pain. This application aims to first produce a map of gene expression comparing native and stem cell-derived sensory neurons from the same donors. The results will show precisely how well stem cell-derived sensory neurons genetically match to their native human sensory neurons counterparts, and therefore these data can be utilized to guide differentiation protocols and improve the validity and interpretability of stem cell-derived sensory neurons. Second, native human sensory neurons and sensory neurons derived from stem cells will be assessed for key functional alterations evoked by chemotherapy-induced neuropathy, a common clinical cause of chronic pain. Here, a functional signaling pathway leading to chronic pain will be sampled in each population of cells to expand knowledge of human neuropathy and determine whether sensory neurons derived from stem cells offer a valid model of neuropathy. This project will uncover the nature of both native and differentiated sensory neurons and significantly advance both models as tools for therapeutic development in chronic pain, neuropathy, and regeneration of the peripheral nervous system.