Cell biological mechanisms underlying stem cell competition

关于干细胞的一种流行观点是，干细胞总是不对称地分裂，从而产生另一种干细胞(自我更新)，而子代则继续产生组织发挥功能(分化)所需的细胞。然而，最近的研究发现，尽管组织整体上存在不对称性，但任何单个干细胞都可以具有对称的结果，这意味着单个干细胞可以分裂产生两个干细胞或两个分化子细胞。平衡是通过确保每当一个干细胞因分化而丢失时，其邻居将对称分裂以取代它(相反，当一个干细胞在对称的自我更新分裂中分裂时，另一个干细胞因分化而丢失)。这意味着每个干细胞都在不断地与其邻居争先恐后地留在支持干细胞自我更新的利基环境中。第二个含义是，随着时间的推移，一些干细胞谱系将占据主导地位，并取代利基中的其他干细胞。这一过程可能会被携带致癌突变的干细胞劫持，这表明这是导致癌症的早期步骤的一部分。我的工作提出要了解干细胞是如何相互取代的，以及是什么使它们决定要么自我更新，要么以牺牲邻居为代价进行分化。我以果蝇黑腹果蝇的睾丸为模型系统，以了解干细胞竞争背后的遗传学和细胞生物学。在我的博士后研究期间，我确定了睾丸中的体细胞干细胞，即所谓的囊干细胞或CySCs，在利基位置经历了随机的替换。此外，增加或减少单个CySC通常从利基接收的信号可能会扭曲该干细胞与其邻近细胞竞争的能力。这些信号分为两类：诱导细胞增殖的信号和促进生长的信号。我发现，增加单个CySC的增殖速度会增加其取代邻近细胞的可能性，同时增加CySC的生长会增加其与邻近细胞相比分化的可能性。作为一个独立的小组负责人，我提议调查基本的细胞过程，即分裂和生长如何控制干细胞相对于其邻近细胞的行为。我将使用只有果蝇才能提供的先进遗传工具，以及实时成像和现代分子生物学方法来可视化、理解和操纵使干细胞在与邻居竞争中或多或少成功的事件。从长远来看，操纵干细胞竞争力的能力将给人类健康带来巨大好处：通过赋予干细胞在市场上的竞争优势，干细胞疗法的效率可以显著提高，因为需要的细胞更少，更多的患病组织可以被工程治疗性干细胞取代。

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.