Angela McDonald

Molecular regulation of the definitive endoderm and its derivatives

The definitive endoderm (DE) develops during gastrulation following the ingression of epiblast cells through the primitive streak ultimately forming the epithelial lining of the respiratory and digestive tracts and their associated organs. DE derivatives such as pancreas, liver and lung are of great interest in regenerative medicine. Some progress has been made in the development of human embryonic stem cell (hESC) differentiation protocols down these DE derivative pathways however robust methods are lacking. Using transcription factors to restrict hESC to DE specific progenitor populations could act to enhance current differentiation protocols.

The overall goal of my project is to understand the molecular mechanisms regulating the specification and differentiation of the DE and its derivatives, in particular, the liver. Our lab has previously shown that the overexpression of SOX17 in hESC results in a stable progenitor line, representing a mesendoerm population. These cells are lineage restricted as demonstrated by their inability to differentiate to ectodermal lineages shown by in vitro and in vivo assays. One aim of my project is to identify additional lineage restricting transcription factors to further restrict these cells to DE and DE derivatives. To do this I will use microarray data to identify potential lineage restricting transcription factors that will be screened in hESC. I will then use genetic and biochemical techniques to characterize the functions of these transcription factors.

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