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Final Report Summary - SPECADE (Specification of anterior definitive endoderm, the role of extracellular matrix and Akt1 signalling)

SPECADE focused on understanding the development of precursors of internal organs such as pancreas and liver. These organs come from endoderm germ layer and SPECADE aimed to understand how the endodermal cells develop and acquire specific identity. In SPECADE we explored the role of the environment outside of the cells and how the environment impacted on cell response to different signals. In particular, we focused on the PI3K/Akt1signaling pathway and its ability to both modulate and interpret signals derived from the environment of the cells. To deconstruct the roles of the environment and Akt1 we used mouse embryonic stem cells and their differentiation as a model for studying the endoderm development.

During embryonic development and linked morphogenesis, cells are constantly changing their surroundings. During SPECADE we found that the environment of the endodermal cells was very dynamic and built by the cells themselves as they began to differentiate. We observed that the environment of cells was not uniform and formed grooves which were low in an important protein Fibronectin. The cells located in the grooves had high levels of E-cadherin, protein known as a cell-cell junction mediator. These grooves formed a unique niche where the precursors were specified and able to undergo subsequent differentiation. We also found that levels of Fibronectin within the cell environment were tightly regulated. We found that both lack and excess of Fibronectin prevented the endodermal specification. Moreover, we found that FN is required for the initiation of endoderm differentiation, but must be degraded to enable the specification of endoderm precursors.
We previously showed that block of Akt1 signaling prevents the endodermal specification. In SPECADE we also found that a simultaneous block to two signaling pathways, Wnt and BMP, can rescue the block to Akt and that the BMP signaling acted on the environment.

In SPECADE we characterized the environment cells differentiate in, its composition and dynamics during endodermal specification and the role of Akt1 signaling in construction of this environment. This is a highly important approach because production of functional cell types from stem cells have not been successful yet. However, a better knowledge of how the three dimensional (3D) environment impacts on cell differentiation could result in improved approaches to producing functional cell types. In SPECADE we described the means by which cells manipulate and later exploit their environment, by characterizing the unique 3D grooves produced by differentiating cells. We also showed how these grooves are required to maintain cell-cell interactions. While a large amount of ESC differentiation studies largely explored the role of signaling in the absence of a cellular context, we attempted to understand the means by which signal transduction influences a cell environment and how the environment impacts on the cells response to signaling.

Endoderm is a crucial tissue giving rise to internal organs such as pancreas and liver. Diabetes is the most prominent disease of pancreas from which millions of people suffer world-wide. Functional cells producing insulin derived from stem cells has the potential to be used in the treatment of diabetes. However scientists have not succeeded in producing efficiently the final state of endodermal cells which could replace the malfunctioned diabetes cells and therefore a better understanding of differentiation is required. In SPECADE we harmonized studies of endodermal development and differentiation with a characterization of a cell environment and crosstalk between them. The work undertaken in SPECADE showed the environment of the cells is highly important and could be a key how to help to produce the functional cell types from endoderm.

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