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dc.contributor.authorAvery, John Welch
dc.description.abstractHuman pluripotent stem cells (hPSCs) are powerful tools to aid in the interrogation of the mechanisms of pathology of developmental disorders as well as modeling the development of embryonic and adult tissues. In this work, we attempted a patient-specific disease in a dish model of the craniofacial disorder Treacher Collins Syndrome (TCS) and the directed differentiation of brown adipocytes from hPSCs. The TCS model was unable to replicate the expected phenotype of reduced neural crest cell numbers or migratory potential. This shortcoming has been putatively attributed to reducing and high antioxidant conditions of the culture medium. Modulating brown adipocyte activity in humans has become an attractive therapeutic target for obesity and related metabolic disorders such as type 2 diabetes. Murine models suggest the brown adipose organ is capable of significant changes in body mass and circulating levels of insulin and glucose. Methods to interrogate human brown adipocyte functionality have been based on adult primary cells or overexpression systems. Here we report a robust and efficient chemically-defined method to differentiate human pluripotent stem cells into brown adipocytes through a developmentally appropriate paraxial mesoderm intermediate. These adipocytes display characteristics of mature brown adipocytes including marker expression, responsiveness to stimulation, enhanced metabolic activity, thermogenic capacity, lipolysis, and utilization of fatty acids. These cells are capable of being maintained in culture for several weeks, are amenable to passage, and upon transplantation in mice can give rise to adipose depots that maintain both morphological and functional properties. We propose that these cells are appropriate for modeling brown adipocyte development in vivo, elucidating basic biological cell fate decisions and branch points and as a platform for high-throughput drug screening to identify putative therapeutic targets to combat obesity and related disorders.
dc.subjectBrown adipocytes
dc.subjecthuman pluripotent stem cells, induced pluripotent stem cells, neural crest cells, paraxial mesoderm
dc.titleModeling treacher collins syndrome and directed differentiation of brown adipocytes from human pluripotent stem cells
dc.description.departmentBiochemistry and Molecular Biology
dc.description.majorBiochemistry and Molecular Biology
dc.description.advisorStephen Dalton
dc.description.committeeStephen Dalton
dc.description.committeeRichard Steet
dc.description.committeeAmar Singh
dc.description.committeeTakahiro Ito

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