CFED · Unravelling the mechanisms regulating cellular fitness during embryonic development

Unravelling the mechanisms regulating cellular fitness during embryonic development

The aim of this research project is to understand the mechanisms that eliminate unfit pluripotent stem cells in the early embryo. During the early mammalian embryogenesis, the cells from the embryo initiate differentiation to form all the tissues of the future organism and a number of quality control mechanisms takes place. Previously, Tristan Rodriguez group has reported that cell competition plays this quality control role in that in this moment of development. Cell competition is a type of cell-cell interaction process by which the less-fit cells are eliminated and the best-fit cells remain. Cell competition was first discovered in Drosophila and, since then, has been reported to happen in other organisms including mammals. Cell competition has been reported to be a key process for development but is also relevant to the application of these cells to regenerative medicine. In addition, the potential implications of this process transcend these roles because, as a mechanism to identify and eliminate abnormal cells, cell competition provides a mechanism to control cellular fitness in a wide variety of situations. This is why cell competition is suggested to be a key mechanism for development, organ size, regeneration and even cancer. The main objective for this project was to investigate the importance of mTOR pathway in the cell competition process that takes place during early mammalian embryogenesis. We planned several specific objectives that were: functionally test mTOR importance in this context, identify what leads to mTOR changes prior to the competition and understand the mechanisms that governs this process. Our data indicates that during the competition between pluripotent stem cells, mTOR levels determine which cells will survive and which will be eliminated. We have increased our knowledge about the mechanisms by which mTOR performs these roles and the nature of the signals that cause the differences in mTOR to arise in the first place. All the experiments have been complemented with unbiased approaches to discover and characterize new pathways involved in cell competition. This is particularly important, as cell competition is a broad term, likely to encompass diverse processes in different tissues, but all leading to similar outcomes. These approaches together result in a deeper understanding of what makes loser cells less fit, and how this state is communicated across and within competing cells, resulting in their elimination. In addition, new signals and pathways involved in cell competition have been arising from this work and also provide a way in which the findings of this study can be readily extended to different cell types and tissues, and therefore have a broad impact.

Data: CORDIS, © European Union