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

干细胞通过产生新的干细胞和分化的子细胞来维持成体组织。这种产生不对称子细胞的能力并不意味着每次分裂都是不对称的：事实上，包括我自己的果蝇在内的许多生物的研究表明，干细胞的分裂导致随机结果。一些分裂导致产生两个干细胞，而另一些干细胞则失去分化，尽管在群体水平上这两种命运是精细平衡的。其结果是，单个干细胞不断相互竞争，以保持在支持其自我更新的微环境或生态位中。这种自然替换的过程可能被携带致癌突变的干细胞劫持，导致这些干细胞和它们的子细胞在干细胞库中定居。我的研究旨在了解干细胞是如何相互替换的，以及是什么导致了它们自我更新或分化的决定。特别是，我试图确定1)来自环境的信号如何通过促进其增殖能力使干细胞更具竞争力，以及2)生长促进信号如何诱导干细胞分化。在我目前的MRC职业发展奖的过程中，我一直专注于细胞周期在调节干细胞自我更新或分化决策中的作用。我们发现细胞周期依赖性转录通过调节细胞代谢协调细胞周期退出和分化，使增殖细胞具有与分化不相容的代谢状态。此外，我们发现干细胞和它们的生态位之间的交流是双向的：生态位监控它所支持的干细胞的增殖。如果检测到缺陷，小生境细胞可以进入细胞周期，并通过反分化补充干细胞库。我们进一步表明，这种交流在正常衰老过程中被破坏，导致生态位随年龄的衰减。其次，通过研究分化促进信号，我们确定干细胞的分化需要一个可逆的启动步骤，然后是不可逆的承诺。我们表明，这两步过程允许分化在组成果蝇睾丸、体细胞和生殖系的两个谱系之间协调。我的奖学金有两个突出的目标，由于在不同机构之间转移以及新冠肺炎疫情及其后果导致实验室中断，我选择搁置这两个目标，直到我有时间收集所需的数据。这些目标是确定使干细胞具有高度竞争性的信号的下游目标，并确定除了转录之外，翻译是如何影响离开生态位的决定的另一层控制。完成这些目标将使我能够全面了解调节干细胞竞争的过程，从控制这种行为的信号到对细胞生物学的下游影响，以及控制基因表达以影响命运决定的机制。因此，过渡支持奖将是建立我的小组在干细胞竞争领域的前沿的关键一步。

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.