Haematopoiesis in a Dish: From Tissue Dynamics to Molecular Mechanisms

成年人平均每秒产生200多万个新血细胞，以取代因自然循环和/或对抗传染病而失去的红细胞和白细胞。这种持续的补充是由所谓的干细胞和祖细胞介导的，这些细胞寿命很长，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。这种所谓的造血过程需要精细地平衡，因为血细胞生产不足或过剩都会导致贫血和白血病等严重疾病。在个体基因和蛋白质的微观尺度上的研究已经确定了许多造血的调节因子。然而，很难从这个微观尺度推断出整个血液系统的功能。研究资助者已经认识到这个瓶颈，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，我们建议将最新的细胞培养技术与数千个单细胞的分子分析相结合，以产生一个多尺度的血液形成模型，明确地将微观和宏观尺度连接起来。拟议的研究将开发一个平台，用于测试白血病患者基因突变的宏观后果，以及测试新的候选药物。此外，建立这个血液平台将为建立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.