Understanding the regulation of adult stem cell migration during regeneration.

Throughout our lives the cells in our body actively maintain our tissues and organs by dividing and moving to replace aged or damaged cells. Cells can be damaged by normal wear and tear, by physical damage like a cut or a burn or because of various diseases. Much of this repair and maintenance is carried out by a special set of cells called "stem cells" that make the cell types in our bodies, as and when required. We now think that much of the aging process, many developmental disorders and in fact many cancers are caused by stem cells going wrong. Damage to the DNA of stem cells can lead to them being unable to divide further to help maintain our tissues and organs leading eventually to aging, but even more importantly this damage can also lead to changes in how stem cells behave so that they over proliferate and over migrate to cause cancer. So understanding how stem cells maintain tissues and the factors that can contribute to them going wrong is important. In this project we are specifically interested in how stem cells migrate correctly to the site of a wound and what can go wrong during this process.
In order to study this we are using a simple animal model system that is capable of amazing regenerative feats because of a population of adult stem cells, that allow it to regenerate all adult tissues and organs, including the brain. These stem cells in these animals, called planarian worms, can be more easily and ethically accessed and studied than the stem cells of more complex animals. As many genes have been conserved over evolutionary time what we have discovered working with planarians continues to provide useful insights into our own biology. For example, we have recently described new genes and genetic interactions that are directly relevant to humans cancers. We have also found out that the process of migration can in itself cause damage to the genes of migrating stem cells during normal migration, as the physical progress of cell migration causes stress upon the nucleus that contains the genome. It is important that this damage is repaired properly as cells migrate, and our data so far indicate that without repair migration stops.
We will use state-of-the-art molecular approaches to understand the how normal stem cell migration is controlled at the genetic level and what happens to this normal control when stem cells in planarians over-migrate to form tumor-like outgrowths.We will also investigate the interplay between cell migration and DNA repair, as this could be particularly important as a potential source of previously unappreciated source of damage to stem cells. The findings of out project will provide new fundamental insights into processes relevant to human diseases, including cancer.

This project aims to understand the regulation of stem cell migration during regeneration, using planarians as a model system. Aspects of our previous MRC funded work have demonstrated that i) stem cell migration to a wound site requires conserved epithelial to mesenchymal transition (EMT) transcription factors, ii) that loss of tumor suppressor function is accompanied by uncontrolled migration, and that iii) migration both leads to increased DNA damage in stem cells and requires active DNA repair mechanisms to proceed.
The recent novel observation that migrating stem cells in vivo encounter DNA damage , called migration-coupled DNA damage (MCDD), suggests migratory activity is a potentially novel source of significant genome instability that may underpin both transformation and/or aging of animal stem cell populations. However, as yet we do not understand the gene regulatory network (GRN) controlling normal stem cell migration during regeneration, the changes in this that lead to over-migration as tumor suppressor mechanisms fails, or how the regulation of migration and DNA repair may interact during normal migration.
In this project we will perform functional genomic experiments, combining RNA-seq, ATAC-seq and RNAi knockdown with detailed observations of stem cell migration, to advance our understanding of these processes. Using RNA-seq and ATAC-seq we can establish the sets of regulatory changes that underpin migration, that lead to over-migration and that are shared between migrating cells and this that are repairing DNA damage. This will allow us to then build and test a GRN to better understand the mechanisms controlling these processes. Ultimately this work will reveal conserved regulatory interactions relevant to human disease processes.

Our research in this project has the potential to dramatically push forward our fundamental understanding of the causes of both normal biological aging, many human diseases and disorders that might be caused by loss of genome stability or defects in cell migration and novel processes that lead to cell transformation and cancer. From this perspective the whole of society stands to benefit from the future benefits to health and well being that this new knowledge may bring. While cell migration has been studied extensively, stem cell migration during regeneration has not been. In addition our work builds on the novel observation that normal cell migration in the context of a living animal can cause damage to the genome, and that while normally this damage is repaired if is not cell migration stops. Thus while it is difficult to foresee the long term impacts of our work it will potentially be part of a body of research that makes a fundamental step forward in our basic understanding of the molecular and cellular basis of some human disease processes. This may provide new avenues for therapeutic approaches that are not currently appreciated. The first step in this pathway will be making sure that the worldwide scientific community is aware of our work. To achieve this we will make our work available on pre-print servers, publish our work in open access journals, make use of social media platforms to publicize our findings, prepare press releases to appropriate media outlets and the MRC and University of Oxford press offices so they can aid us in publicizing our findings to the broader public (which includes the worldwide scientific community).

Our research will lead to the training and skills development of early career researchers who will then be well placed to contribute to economic impact. The post-doctoral researcher will for example develop state-of-the-art data analysis skills and as well as develop generic transferable project management and presentation skills. While most trainees in the lab stay in academic research, others have gone into research industry and some have transitioned into business management. Both the specific research and transferable skills training the two team members in this project will receive, will prepare them to make excellent contributions in academic or non-academic settings.

Through our pathways to impact activities we hope to better inform and involve the public in our research. Our previous experience had led to realize that the planarian research model is a very attractive vehicle for this process. In particular we have found that science A-level students can be actively engaged in the research process, and have received positive feedback that this increases the likelihood of them pursuing a science degree at University and considering scientific research as career. During our project we will take the opportunity to engage high school science students with the research process by getting them to perform and record the results of simple regeneration experiments in the classroom.