Cell biological mechanisms underlying stem cell competition

A popular view of a stem cell is that it is a cell that always divides asymmetrically to give rise to another stem cell (self-renewing) and a daughter that goes on to give rise to cells that the tissue needs to function (differentiation). However, recent work has found that although there is asymmetry within a tissue as a whole, any individual stem cell can have symmetric outcomes, meaning a single stem cell can divide to give rise to two stem cells or two differentiating daughters. Balance is achieved by ensuring that whenever a stem cell is lost to differentiation, its neighbour will divide symmetrically to replace it (and conversely, when a stem cell divides in a symmetrical self-renewing division, another is lost to differentiation). This means that every stem cell is constantly jostling with its neighbours to remain in the niche, the environment that supports the self-renewal of stem cells. A second implication is that, over time, some stem cell lineages become dominant and replace the others in the niche. This process can be hijacked by stem cells carrying tumour-inducing mutations, suggesting that it is part of the early steps that lead to cancer. My work proposes to understand how stem cells replace each other, and what biases their decision to either self-renew or differentiate at the expense of their neighbours. I use the testis of the fruit fly, Drosophila Melanogaster, as a model system to understand the genetics and cell biology that underlie stem cell competition. During my postdoctoral work, I established that the somatic stem cells in the testis, called cyst stem cells or CySCs, undergo stochastic replacement at the niche. Moreover, increasing or decreasing signals that a single CySC normally receives from the niche can skew that stem cell's ability to compete with its neighbours. These signals fall into two classes : cell proliferation-inducing signals and growth-promoting signals. I found that increasing the rate at which a single CySC proliferates increases its likelihood of replacing its neighbours, while increasing the growth of a CySC increases its likelihood of differentiating compared to its neighbours. As an independent group leader, I propose to investigate how the basic cellular processes that are division and growth control the behaviour of a stem cell relative to its neighbours. I will use a combination of the advanced genetic tools that only Drosophila can provide, along with live imaging and modern molecular biology approaches to visualise, understand and manipulate the events that make stem cells more or less successful at competing with their neighbours. In the long term, the ability to manipulate the competitiveness of a stem cell will bring great benefits to human health : by giving a stem cell a competitive advantage in occupying the niche, the efficiency of stem cell therapies could be significantly enhanced, as fewer cells would be needed and more diseased tissue could be replaced by the engineered therapeutic stem cells.