Immortal worms and stem cells: how do planarians replace and rescale during regeneration?

Growing a new head, arm or leg is something humans obviously can’t do. But we do have cells that have some capacity to generate other cell types when they are needed, for example in response to cuts or bruises we are able to heal and replace damaged cells. In this study, a planarian worm will be used to understand the basic biology of stem cells, regeneration and healing. Planarians have a large number of stem cells which are capable of giving rise to every other cell type. For example, if a planarian is cut into small pieces, these cells will allow each piece of the worm to regenerate into a whole new, albeit smaller, worm. The intention of this research is to understand how the planarian worm’s stem cells are able to divide and give rise to the right cells at the right place in the new worm. If we can understand this process we may be closer to understanding our own capacity to regenerate lost or damaged cells. This type of research is particularly important for understanding diseases in which cells have been lost or damaged and new cells are needed (such as Alzheimers), or for diseases like leukemia where our own stem cells go haywire and divide too quickly and/or produce the wrong types of cells.

Planarians are a classical model for regeneration and stem cells. They regenerate to form complete animals from body fragments. This requires the complete re-specification of positional information, proliferation and differentiation of neoblast stem cells to replace missing tissues and the generation of energy and materials from existing resources. The development of molecular genetic technologies and a whole genome sequencing project for the planarian Schmidtea mediterranea, provide a model system to understand animal stem cell biology. Stem cells and regenerative capacity are apparent throughout the metazoa and a detailed understanding of these processes in a model organism are likely to be relevant to higher organisms. We will take three synergistic approaches to identify essential genes for positional specification, the rescaling of preexisting tissues and the breakdown of existing cells to provide energy during regeneration. Firstly, we shall take a candidate gene approach by identifying genes known to be important for positional information and differentiation in other animals during embryogenesis as well as genes involved in mobilizing resources during starvation. RNAi in combination with regeneration assays will be used to assess possible roles for these genes during both normal homeostasis and regeneration. A second approach will be to compare levels of gene expression in regenerating planarian tissues at different times and positions along the body axis using microarray expression analyses. RNAi will also be used to investigate the function of these genes during regeneration and homeostasis. Where appropriate we will use the planarian transgenic system to further investigate the function of genes identified in these two approaches. Finally, to investigate the signals that confer correct identity during head specification we will employ transplant experiments that subvert normal regeneration. When a head region of one planarian is transplanted behind an anterior cut that would normally generate a new head region it will inhibit head formation and induce a tail region instead. This experimental system will be used to identify the nature of the inhibitory signal from transplanted heads and how it reprograms positional identity at an anterior site of regeneration. RNAi and transgenesis will allow us to selectively manipulate gene expression in both host and donor animals to allow us to understand the reprogramming capacity of the head signal. The combination of these approaches will provide insight cues required for stem cells to differentiate correctly and how these are linked to pathways that control metabolism, energy production and self-renewal.