Multiscale dynamics of mammary gland remodeling

Most cells in our bodies are constantly replenished. For instance, the cells in our skin or intestine are almost completely renewed every week, by populations of dividing stem cells which compensate for the normal shedding of differentiated cells. The nature, dynamics and regulation of these stem cells has been a topic of intense interest in the past decade, both from a fundamental biology perspective, but also to get more insight into how we could help regeneration. Key outstanding questions in the field include: i) are many cells endowed with such renewal and regeneration potential, or is it the property of only very rare dedicated cells? ii) what are the molecular and physical signals that tell a stem cell to behave in a certain way, for instance dividing or differentiating to replace a dying cell of a certain type? Even more strikingly, some organs not only display local cellular turnover during our lifetime, but also global and extensive changes in organ shape and morphology. As a prime example of striking and continuous organ remodeling throughout adulthood, we plan to study the mouse mammary gland. The mammary gland is a highly branched, tree-like organ, which is highly responsive to systemic hormonal signals. Although its large-scale organization is laid- down during puberty (through a process called branching morphogenesis of sequential tip- driven branching gradually increasing shape complexity), the mammary tree is extensively remodeled, via branch initiation and regression, during each estrous cycle. However, we still dont understand well the global and local rules underlying these remodeling events. What determines that a specific branch in the mammary gland will grow or regress at a given cycle? What are the local cellular behavior and physical forces that underlie these global changes? These questions are very hard to answer based on current data, which is largely static and population-level, i.e. not allowing the continuous imaging of one mammary gland evolving in time. Here, we will combine the expertise of two groups, respectively in experimental stem cell/developmental biology and theoretical biophysics, to answer these questions. On the theoretical side, we will develop physical and mathematical models of the forces exerted by individual cells and of their decisions to divide/differentiate. On the experimental side, we will use live intravital microscopy to look at how a given mammary gland evolves over time, and thus produce a spatiotemporal map of branching remodelling, ranging from the whole-organ scale to the cellular level. Unravelling the dynamics and mechanisms of mammary gland renewal and remodelling will be a major step toward our understanding of tissue maintenance, with potential application in other tissue contexts.