Deciphering the specific role of signalling and the niche in which cells develop and differentiate is one of the central problems of developmental biology. Approaching this problem has been difficult in vivo, as embryonic development involves complex signalling machinery directly instructing the cell fate, or influencing the environment which itself drives the cell specification. Embryonic stem (ES) cell technology affords a new approach, allowing in vitro reconstitution of elements guiding cell differentiation in a defined manner. ES cells can therefore be used to break down developmental decisions and understand the molecular basis of cell fate choice.
In SPECADE, I will use mouse ES cells to analyse the signalling underlying differentiation of anterior definitive endoderm (ADE), the precursor of the ventral foregut and a number of visceral organs including pancreas and liver. I will build on previous work at the hosting Brickman laboratory, which has recently shown an unexpected role of extracellular matrix (ECM) in patterning the definitive endoderm. Revealing, that Fibroblast Growth Factor and coupling PI3K/Akt1 signalling pathways act both in vitro and in vivo to regulate protein level of Fibronectin in the ECM.
The aims of my project are therefore to identify and understand the mechanism by which PI3K/Akt1 signalling modifies the ECM composition and how the specific ECM induces the anterior character in the endoderm. SPECADE’s approach is to study ES cells as a whole system, including its surrounding environment. This will enable us to understand and recapitulate in vivo development, bringing us closer to successful generation of functional cell types in vitro, such as hepatocytes and pancreatic beta cells. This can be used therapeutically for the treatment of diseases such as diabetes and cancer and is one of the main objectives of the current research at the hosting institute, the Danish Stem Cell Center (DanStem).
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