Haematopoiesis in a Dish: From Tissue Dynamics to Molecular Mechanisms

在一个普通的成年人中，每秒产生超过200万个新的血细胞，以取代通过自然周转和/或对抗传染病而失去的红细胞和白色血细胞。这种不断的补充是由所谓的干细胞和祖细胞介导的，这些干细胞和祖细胞是长寿的，可以分裂以扩大它们的数量，并产生超过10种不同的专门类型的血细胞。这个所谓的造血过程需要保持良好的平衡，因为血细胞的生产不足或过多会导致严重的疾病，如贫血和白血病。对单个基因和蛋白质的微观尺度研究已经确定了许多造血调节因子。然而，很难从这种微观尺度推断整个血液系统的功能。研究资助者已经认识到这一瓶颈，因此现在优先考虑旨在跨规模连接的研究工作，期望加速基础研究和药物发现过程。在这里，我们建议将细胞培养中的最新技术与数千个单细胞的分子谱分析结合联合收割机，以生成血液形成的多尺度模型，明确地将微观和宏观尺度跨时间联系起来。这项拟议的研究将开发一个平台，用于测试白血病患者中发现的基因突变的宏观后果，以及新药候选物的测试。此外，建立这个血液平台将为其他主要器官及其相关疾病的类似研究工作提供蓝图。

In an average adult, over 2 million new blood cells are generated every second, to replace red and white blood cells lost through natural turnover and/or fighting infectious diseases. This constant replenishment is mediated by so-called stem and progenitor cells, which are long-lived, can divide to amplify their numbers, and give rise to over 10 different specialised types of blood cells. This so-called process of haematopoiesis needs to be finely balanced, because under- or overproduction of blood cells can cause severe diseases such as anaemia and leukaemia. Research at the micro-scale of individual genes and proteins has identified many regulators of haematopoiesis. It is however difficult to extrapolate from this micro-scale to the functionality of the entire blood system. Research funders have recognised this bottleneck, and therefore now prioritise research efforts aiming to connect across scales, with the expectation of accelerating both basic research as well as the drug discovery process. Here we propose to combine the latest technologies in cell culture with molecular profiling of thousands of single cells to generate a multi-scale model of blood formation, explicitly linking the micro and macro scales across time. The proposed research will develop a platform for testing the macro-scale consequences of gene mutations found in leukaemia patients, as well as the testing of new drug candidates. Moreover, establishing this platform for blood will provide a blueprint to set up analogous research efforts for other major organs and their associated diseases.