Epithelial Sheet Dynamics during Primitive Streak formation as Active Matter

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

This study focuses on characterising the signals and cellular mechanisms that drive gastrulation in the chick embryo, closely combining experiments and physical modelling. Using advanced Light Sheet Microscopy imaging we have shown that the large-scale tissue flows that drive streak formation result from complex spatiotemporal patterns of shape changes, ingressions and intercalation of mesendoderm cells. While appearing stochastic at the cell-level, these events result in highly robust behaviour at the tissue level. Our experiments strongly suggest that myosin-dependent mechanical cell interactions play critical roles in the spatial coordination of these behaviours. We will now further characterise these cellular interactions experimentally and use concepts and modelling methods from soft active matter physics to understand emergence of the global behaviour. Specifically we will further develop computational methods to detect and quantify the direction and frequency of cell intercalations during streak formation. Using a combination of laser cutting, local and global mechanical perturbation experiments we will investigate whether these intercalations are tension dependent resulting in elastic propagation. We will address the role of tension-dependent MyosinII cable assembly in elastic propagation and begin addressing the signalling pathways that control it. Characterizing the spatiotemporal patterns and mode of mesendoderm cell ingression will allow us to assess their role in tension generation and address whether secreted factors are involved in the integration of these mechanical processes. These experimental results will feed into soft active matter models at the cell and at the continuum scale, that will allow us to understand how individual disordered cell behaviours lead to highly organised behaviour at the tissue level. Embryo-scale simulation will allow us to explore parameter regions not readily accessible to the experiment and guide experimental design.

The research proposed here investigates the mechanisms governing gastrulation, a central process in the development of all higher animals. Findings made here will greatly increase our understanding of how cell-cell signalling directs cellular events, like differentiation, proliferation and migration. This is important for understanding development and the origin and cause of many congenital defects. Gastrulation is core material in many Life Sciences and Medical textbooks. Key research findings made here could become textbook material and therefore affect students of the medical and life sciences.
Soft and active matter are recent directions within the physical sciences. They are specifically set up to deal with out of equilibrium, living systems and the patterns they form. As such, the research proposed here forms part of a concerted effort to construct a general theory of living things, in this case the collective properties of cells behaving as a tissue. Development, with its germ layers, patterning and segmentation, and geometrical constraints, is one of the most promising areas for this approach. Research findings from this proposal are expected to find their way into teaching materials for students in the new, interdisciplinary field of biological physics / quantitative biology.
The key processes of gastrulation such as directed collective migration, ingression and EMT are also central to other biological processes using similar cellular mechanisms like wound healing, tissue repair and regeneration. Failure to properly control these is key to the development of autoimmune diseases and metastasis of cancer cells. Therefore findings made here will be directly relevant to these areas. Understanding these developmental processes is also essential for the rational use of embryonic stem cells in regenerative medicine. It is by no means clear how embryonic stem cells migrate to the right positions and organise themselves correctly to repair defects in-situ. Clearly, successful manipulation of stem cells will require understanding of directed cell migration, cell-cell interactions and interactions between behaviour and signalling. Therefore, in the 5-10 year term, the research proposed here will undoubtedly have practical applications in these increasingly important areas of medicine and healthcare, affecting researchers and practitioners in both the academic and the commercial sector.
An important aspect of the proposed research is that it will strengthen links between the Biology and Physics communities. This closer integration will be beneficial to both: Biology will benefit from the depth of modelling experience, and wealth of analytical and numerical techniques developed in the statistical mechanics community, and Physics will benefit from opening up to a new community and gaining impact on a rapidly developing area. A vital aspect here is the development of a productive interdisciplinary culture. Though this is accepted reality, current undergraduate and postgraduate training remains largely monodisciplinary. Important interdisciplinary training will be provided to the PDRAs involved as well as associated PhD and master students. For example, Dr Manli Chuai was trained as a medical doctor but is now also trained in methods of advanced LSFM and large scale data analysis. Hence, an important added benefit of our proposed research will be to develop careers within an interdisciplinary culture.
The Life Sciences sector has an important economic impact in Dundee, contributing around 16% of the city's GDP. A range of activities and organisations in the city connect scientists with the public. In recognition of the economic and social impact of these interactions, the College of Life Sciences won the BBSRC "Excellence with Impact" Award in 2011.
Finally, this research generates exquisite experimental and simulated images. These have been and will be part of exhibitions at the local, national and international level.