How tissue mechanics control cell differentiationin vivo

One of the central questions in biology is how a single cell, the fertilized oocyte, is able to generate hundreds of different cell types during embryonic development, like neurons, muscle, blood cells, etc.; answering this questions is not only essential for the biological sciences, but has deep implications in cell therapy. Mastering the transformation of one cell into a different one, called cell differentiation, would allow us to generate specific cell types to replace defective cells during regenerative therapies. For example, in neurogenerative diseases defective neurons need to be replaced by healthy ones that could be generated in vitro by cell differentiation. However, HOW A NON-NEURONAL CELL IS DIFFERENTIATED INTO A NEURON IS POORLY UNDERSTOOD. It is clear that cell differentiation is controlled by diverse cues, such as chemicals and mechanicals. While the role of chemical cues in controlling cell behaviour is comparatively well studied, how tissue mechanics influences cell differentiation remains unknown, especially in vivo, as most of biomechanical studies are performed in vitro.

HERE WE WILL STUDY THE ROLE OF TISSUE MECHANICS ON THE DIFFERENTIATION OF NEURONS DURING EMBRYO DEVELOPMENT IN VIVO.

We have developed special tools to manipulate the mechanical properties of live tissues in Xenopus embryos. We will use these tools to modify tissue stiffness in vivo followed by analysis of neuronal differentiation. In addition we will identify the molecules required to sense and transduce the mechanical cues into in vivo neuronal differentiation. The central aim of this proposal is to elucidate the fundamental principles underlying the interaction between cell mechanics and fate specification during embryo development. We expect that this transdisciplinary approach will provide answers to a central yet unresolved question in developmental biology: how the interplay between cell mechanics and fate specification drives embryo development.

Cell migration and differentiation are central to many biological processes, from embryo development to adult homeostasis, including stem cell physiology and cancer progression. During development hundreds of different cell types are generated. Most of the research on cell differentiation has focused on the genes that control this process, but growing evidence shows that mechanics plays an important role in cell differentiation as well. However, most biomechanical studies are performed in vitro on flat surfaces very different from the complex environment found in vivo. The main reason for the lack of biomechanical studied in vivo is due to the limited technology to measure and manipulate mechanical properties in vivo. Thus, there is an urgent need to study the biomechanics of cell differentiation in vivo as little is known about it despite its importance in embryonic development.

In this project we will develop optogenetic tools and use Atomic Force Microscopy to manipulate and measure tissue stiffness in vivo. We will apply these new technologies to neural crest cells, a highly migratory and multipotent embryonic cell population, to test the role of tissue mechanics on cell fate decisions and differentiation in vivo. We expect that this multidisciplinary project will provide answers to a central yet unresolved question in developmental biology: how cell differentiation is controlled by tissue mechanics during embryo morphogenesis.

In this project we identify the international science base and the general public as beneficiaries beyond the immediate academic community.

Professional and technical training of the PDRA to be appointed on the project will contribute directly to the science base. To achieve maximal impact of the research, we will provide a broad range of scientific training through the combination of internationally recognized expertise brought by the applicants. In addition, professional training will be ensured through the infrastructure provided by the collaborating world-class universities in which the research will be performed.

We aim to identify the mechanism by which tissue mechanics controls cell differentiation during embryo development. We hope to raise awareness to our research among the general public as failure of neural crest differentiation leads to a wide range of syndromes called neurocristopathies, which represent an important fraction of birth defects in England (1.1%; UK Health Research). We will engage the public through the UCL facilities to communicate and disseminate our discoveries to the general public. In addition to interactions with the general media, we plan to produce lay publications and outreach activities aimed at school children. We are currently interacting with a private company to develop video games based on movement of cells that could relate to the general public. We will continue with this kind of activities to ensure that our research will provide major impact in several disparate areas.