IDENTIFICATION OF A NOVEL ANGIOPOIETIN 2 SIGNALLING CENTRE IN THE EMBRYONIC HAEMATOPOIETIC STEM CELL NICHE

造血干细胞，也被称为造血干细胞（hsc），存在于成人骨髓中，并且在整个生命周期中几乎所有的血细胞都是由造血干细胞产生的。多年来，造血干细胞移植已被用于恢复血液疾病和癌症患者的正常血液形成（全世界每年约50,000例患者）。然而，供体严重短缺，登记的患者中只有20-60%的患者找到了适合移植的良好基因匹配，这影响了治疗选择、效率和结果。因此，迫切需要寻找造血干细胞的替代来源。一种解决方案是在实验室中从其他容易获得的细胞类型中制造造血干细胞，例如多能干细胞，它能够在体内制造任何类型的细胞。这种方法对再生医学有很大的希望，但目前在实验室中产生造血干细胞仍然是一个巨大的挑战，主要是因为，尽管对医学科学具有重要的基础意义，但我们对造血干细胞在胚胎发育过程中如何首次出现的了解有限。我们最近的分析揭示了一种新的信号中心，Angpt2，我们发现它是小鼠胚胎中HSC出现的强烈刺激物。我们在人类胚胎中观察到该因子的类似表达模式，表明它可能是一个重要的HSC调控中心，这在以前没有被描述过。在这个项目中，我们将使用尖端技术，包括细胞纯化、基因表达谱、先进成像、生物信息学和移植，对Ang2信号在胚胎中驱动HSC出现的作用进行详细的研究。使用新的基于图像的空间相关方法，我们将建立小鼠和人类胚胎HSC发育中该信号中心的第一个3D数字模型。这些三维模型和相关数据集将成为研究领域的宝贵资源。我们将进一步测试Angpt2是否能增强多能细胞的造血细胞/ HSC生成。从长远来看，这可能有助于开发在实验室生产造血干细胞的方案，以满足临床造血干细胞的短缺。

Blood stem cells, also known as haematopoietic stem cells (HSCs), are found in adult bone marrow and they give rise to practically all blood cells throughout the entire lifespan. For many years, transplantations of HSCs have been used (~50,000 patients/year worldwide) to restore normal blood formation in patients with blood disorders and cancers. However, there is a significant shortage of donors, only 20-60% of patients on registers find a good genetic match for transplants, which affects treatment options, efficiency and outcomes. There is therefore an urgent need to find alternative sources of HSCs. One solution would be to produce HSCs in the laboratory from other readily available cell types, such as pluripotent stem cells, which are capable of producing any cell type in the body. This approach holds great promise for regenerative medicine, but currently generating HSCs in the laboratory remains a big challenge, mainly because, despite being of fundamental importance for medical sciences, we have only limited understanding of how HSCs first emerge during embryonic development. Our recent analyses have revealed a novel signaling centre, Angpt2, which we found to be a strong stimulator of HSC emergence in the mouse embryo. We observed a similar expression pattern of this factor in the human embryo, suggesting it could be an important HSC regulatory centre, which has not been described before. In this project, we will use cutting-edge techniques, including cell purification, gene expression profiling, advanced imaging, bioinformatics and transplantations, to perform a detailed investigation into the role of Ang2 signaling in driving HSC emergence in the embryo. Using novel image-based spatial correlation methods we will build the first 3D digital model of this signaling centre in mouse and human embryonic HSC development. These 3D models and associated datasets will be a valuable resource for the research field. We will further test if Angpt2 can enhance haematopoietic cell/ HSC production from pluripotent cells. In the long term, this could help development of protocols to produce HSCs in the laboratory to meet the shortage of HSCs in the clinic.