Stem cells are essential for development and continued maintenance of tissues and organs. They are characterized by their ability to self-renew as well as to produce differentiated progeny.
Understanding the dual capacity of self-renewal and differentiation is an important aim of regenerative medicine and also has implications for cancer biology. The aim of work in our group is to identify mechanisms important for these processes and ultimately to understand how they function collectively to promote homeostasis of a tissue. To do so, we are using a simplified model system, the Drosophila intestine which contains around 1000 multipotent intestinal stem cells (Fig. 1). The intestinal stem cells produce the two differentiated cell types required for organ function: the enterocytes and enteroendocrine cells. The differentiated cells are replaced approximately once a week in healthy animals but can be stimulated to rapidly regenerate the intestine upon infection by pathogenic bacteria or treatment with damaging agents (DSS, paraquat). Thus, this is an excellent and simple model for mammalian tissues such as the intestine, lung or skin that need to regenerate in response to environmental stimuli.
We are using this model system to address several important questions:
- How is the proliferation of the stem cell regulated?
- What controls the differentiation choice of the stem cell?
- In addition, we are using this model to understand the first steps of cancer initiation: how do somatic mutations arise? What are their consequences on adult stem cells and tissues?
Proliferation control: In order to gain broader insight into proliferation and differentiation control of ISCs, we have conducted an EMS-based genetic screen to identify novel regulators. We are currently focusing on several genes identified in this screen including regulators of chromatin remodeling that are conserved in mammals, mutated in human cancers and are essential in the fly intestine to limit stem cell proliferation.
Differentiation control: Our past work (Bardin, AJ, 2010) has identified the achaete-scute transcription factors as being essential for stem cell differentiation into enteroendocrine cells. We have now identified additional factors controlling enteroendocrine differentiation and are studying their mechanisms of action (Sallé, et al, in press). This will provide insight into how an accurate balance of terminal cell fates is achieved in homeostatic adult tissues.
Spontaneous mutation: We are using the adult fly intestine to understand the mechanisms underlying spontaneous mutation. We have recently shown that intestinal stem cells acquire spontaneous mutations during aging, resulting in frequent mutation of the tumor suppressor gene Notch and driving neoplasia formation (Fig.2). We are using whole-genome sequencing approaches to determine the nature and mechanisms driving stem cell somatic mutation (Fig 3). In particular, we would like to understand the role of diet, pathogenic bacteria, and additional environmental components in promoting mutation.