MRC Transition Support Award: Cell biological mechanisms underlying stem cell competition

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Stem cells maintain adult tissues by giving rise to both new stem cells and to differentiating daughters. This ability to produce asymmetric daughter cells does not mean that each division is asymmetric: indeed, work in many organisms including my own in Drosophila has shown that the divisions of stem cells result in stochastic outcomes. Some divisions result in the production of two stem cells while other stem cells are lost to differentiation, although at a population level both fates are finely balanced. A consequence of this is that individual stem cells are continuously competing with each other to remain in the microenvironment, or niche, that supports their self-renewal. This process of natural replacement can be hijacked by stem cells carrying oncogenic mutations, leading those stem cells and their daughters to colonise the stem cell pool. My research aims to understand how stem cells replace each other and what biases their decision to self-renew or differentiate. In particular, I seek to determine 1) how signals from the environment make stem cells more competitive by promoting their ability to proliferate, and 2) how growth-promoting signals induce differentiation of stem cells.Over the course of my current MRC Career Development Award, I have focused on the role of the cell cycle in regulating the decision of stem cells to self-renew or differentiate. We found that cell cycle-dependent transcription coordinates cell cycle exit with differentiation through the regulation of cell metabolism, such that proliferating cells have a metabolic state that is incompatible with differentiation. Additionally, we uncovered that communication between stem cells and their niche goes both ways: the niche monitors the proliferation of the stem cells it supports. If a defect is detected, niche cells can enter the cell cycle and replenish the stem cell pool through trans-differentiation. We further showed that this communication is disrupted during normal ageing and leads to age-dependent decay of the niche.Secondly, by studying the differentiation-promoting signals, we determined that differentiation of stem cells requires a reversible priming step followed by irreversible commitment. We showed that this two-step process allows differentiation to be coordinated across the two lineages that compose the Drosophila testis, soma and germ line.There are two outstanding aims from my Fellowship that, due to disruptions to the lab following moving between institutions and then the Covid pandemic and its consequences, I chose to set aside until I could dedicate the time to collecting the required data. These aims are to determine the downstream targets of the signals that make stem cells hypercompetitive, and to identify how, in addition to transcription, translation is another layer of control that affects the decision to leave the niche.Completing these aims will allow me to build a full picture of the processes regulating stem cell competition, from the signals that control this behaviour to the downstream effects on cell biology and the mechanisms by which gene expression is controlled to influence fate decisions. Thus, the Transition Support Award will be a critical step in establishing my group at the forefront of the field of stem cell competition.