#	Pagina
attuale pagina	/open-h2020/projects/207843/results.html
-1	/politiche-coesione/progetto/1MPIC-4-FSE-2008-545/index.html
-2	/politiche-coesione/progetto/1LOLOMBGEFO-00000000000024136813/index.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CFED (Unravelling the mechanisms regulating cellular fitness during embryonic development)

Teaser

Summary

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.

Work performed

During this project we have been investigating the importance of mTOR pathway in cell competition during early mouse embryogenesis, both in-vivo and in-vitro. Our data indicates that during the competition between pluripotent stem cells, mTOR levels determine which cells will survive and which will be eliminated. During this project we have been trying to identify mechanism by which mTOR performs these roles as well as establishing the nature of the signals that cause the differences in mTOR to arise in the first place. These 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 will 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. The new signals and pathways involved in cell competition discovered during this project will 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.

Some results that were produced over this project have already been published in scientific journals. The main results achieved during this project are going to be published soon this year 2019 and some of them have already been presented in some scientific conferences. In addition, the data produced during this project has helped us to start new branches of investigation and some of them are already producing interesting results.

Final results

In the first place, the results generated from this project (published or about to be published) will improve the knowledge in the field of cell competition and developmental biology. Cell competition is a quality control mechanism to ensure that the cells are ideal and to eliminate defective cells. That means that cell competition could have a key role or could help to understand a variety of processes like development, organ size, tissue homeostasis or even cancer. In addition, the results from this project have already been presented in scientific conferences and this has created a branch of key collaborations which will help to further develop our ideas.

The primary beneficiaries and users of this research are members of the academic sector â€“ scientists, teachers and students. Other beneficiaries are the general public and commercial sector. The advent of human embryonic stem cell (hESC) technologies provides a promising avenue for providing cells for stem cell therapy. Therefore, the data obtained in this project will benefit companies developing hESC-based cell types for this purpose. Cell competition provides a mechanism to eliminate defective stem cells, and thus our results will be help provide better quality cells for stem cell therapy. Further, the high death rate of hESCs in culture is hampering efficient expansion of these cells for applications such as regenerative medicine and disease modelling. Mechanistic understanding of hPSCs poor in vitro survival will inform the companies that develop media for hESC maintenance in their efforts to develop cell culture media products that can optimise stem cell fitness and are more suitable for clinical, and high-throughput screening applications. Thus, the outputs from this project could inform the translational pipeline of the pharmaceutical and biotech companies developing hESC-based cell replacement therapies for treatment of degenerative diseases (e.g. Advanced Cell Technologies, Viacyte). The output from this project will be particularly relevant to the UK Regenerative Medicine Platform (UKRMP), established with the goal of tackling hurdles that are currently hampering translation of basic scientific discoveries on stem cells into clinical use.

Although it is not readily expected that the research outlined in this proposal will lead to a commercial product, we remain alert to such a potential outcome. Imperial College Innovations will protect and exploit the intellectual property (IP), ensuring that any new ideas/discoveries are suitably protected; by facilitating patent protection, undertaking all aspects of negotiations required when entering into any agreements with commercial organizations and advising on the best plan of action for IP exploitation.