Discovering novel regulators of stem cell behaviour in a highly regenerative context

Lead Research Organisation: University of Oxford
Department Name: Zoology

Abstract

The whole of biomedical research is underpinned by key detailed experiments performed in simple model organisms. These animals provide relatively cheap and rapid systems in which to make novel discoveries, with nearly all fundamental cell and molecular biomedical processes having their first genetic description in either the fruit fly Drosophila melanogaster or the nematode Caenorhabditis elegans. This is because all metazoan animals share conserved evolutionary features that were present in their last common ancestor. The reason that these two model organisms have been so extensively used is that historically they were amenable to genetic analysis. In the last twenty years a plethora of new ways of studying how genes work have been invented such that it is possible to study many other animals in great detail. As these animals have all evolved independently it is possible for them to have features in common with our own biology that the established models do not. For example, neither the fruit fly nor the nematode make extensive use of adult stem cells during their life history in contrast to mammals.
Here we propose to use planarians, another simple animal that does use adult stem cells as part of its life history. These animals can use their stem cells to regenerate their whole body, including the brain. This is because their adult stem cells are able to divide and make new tissues almost indefinitely and we have already shown that some of the genes controlling planarian stem cells are likely to have conserved functions in humans. Many of these genes may have roles in human diseases when they are mutated to become over or under active We would like to find these genes and describe their functions in controlling stem cell biology as this is likely to be very informative about what they might do in humans and how they might be involved in disease proceeses, particularly those cancers that originate from from rogue adult stem cells in mammals form tumors.
In order to achieve this we have designed a sensitive and rapid method forstudying the function of novel genes both in adult stem cells and in their environment, as both are likely to be important for understanding how stem cells behave and mistakes this behaviour can lead to human diseases, particularly cancer.

Technical Summary

Planarians are capable of profound regenerative feats, such that even small tissue fragments containing none of the major organs systems can regenerate to form complete animals. This regenerative potential is fuelled by a population of highly proliferative pluripotent adult stem cells that proliferate to produce post-mitotic progeny that replace missing distal structures in a regenerative blastema and contribute to reforming and rescaling organs with thin existing tissues. This requires exquisite control of stem cell proliferation levels, the balance between symmetric and asymmetrical cell division, differentiation into the correct cell types at the correct location and migration. These basic cellular behaviours are of key importance for human disease processes, particularly cancer. Given the understudied phylogenetic position of planarians it is timely to utilise them as a simple model system to make novel discoveries by screening for novel physiological functions for conserved genes.
We have designed an assay that makes use of the classical observation that when proliferating stem cells are removed by planarians by X-ray irradiation of part of the animal the remaining stem cells are readily able to rescue the irradiated tissue. This approach allows us to observe stem cell behaviour as they migrate into and populate a "blank canvas" of differentiated tissues. By observing and quantifying the behaviour of stem cells and progeny as they repopulate the irradiated region we can make predictions about the interactions between proliferating cells and their recent progeny post-mitotic progeny and differentiated cells in regulating the tissue micro-environment to facilitate stem cell reconstitution. We will combine transcriptomic and proteomic expression analysis of the blank canvas as stem cells migrate and begin to reconstitute the irradiated region with an RNAi based screen of gene function to identify novel genes involved in controlling key stem cell behaviours.

Planned Impact

Away from immediate academic beneficiaries other model organism researchers and evolutionary biologists will benefit from our activity on this project, particularly those researchers broadly interested in stem cell biology and cancer research. Beyond other academics in the immediate area our findings will be directly relevant to large and growing part of the industrial biomedical sector that is becoming more focused on stem cell biology. This is a large field with clear potential medical applications as evidenced by the number of commercial medical, biotech and biopharmaceutical studies that are actively researching stem cell biology and compounds that effect stem cell maintenance. We will contribute by describing stem cell biology in an invertebrate system, that has life history traits suggesting special adaptations in telomere maintenance. More specifically we will be investigating a scenario where t adult stem cells are potentially immortal without apparently predisposing to tumours. We also believe that given the conservation of molecular mechanisms between phyla planarian species may be excellent systems in which to assay potential drugs relevant to stem cell biology, our work will establish evidence as to whether this is a viable possibility.


Our research is basic biomedical research and we realise the importance of explaining to the public why what may appear quite abstract (working with worms) is actually rather important for understanding of key processes that are relevant to human disease processes. For this reason the AAA lab engages in extensive public engagement and outreach through our website, through talks, visits to schools and societies and through YOUTUBE videos. For example AAA YOU TUBE views are well in access of 200,000 views. This work provokes questioning, debate and awareness in society. Performing a Google search will demonstrate the plethora of media coverage and public interest our work has generated through our public engagement work. This effort shows one of the pathways to impact we take in addition to our research.
We will continue to present our work at conferences, events and in the media to ensure the public knows what they are paying for. As opportunities arise we will also investigate whether our model system can be used in industry, for example to screen compounds that block or promote stem cell activity.


We will measure success of our pathways to impact by recording the feedback we get from society at large, and where appropriate answer questions or enter into wider debate about the impact of our work and of others in our general research area.

Publications

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