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

血液干细胞，也被称为造血干细胞(HSCs)，在成人骨髓中发现，它们几乎在整个生命周期中产生所有的血细胞。多年来，造血干细胞移植(全球每年约50,000名患者)被用于恢复血液病和癌症患者的正常血液形成。然而，供者严重短缺，登记在册的患者中只有20%-60%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，迫切需要寻找替代的人类干细胞来源。一种解决方案是在实验室从其他容易获得的细胞类型中培养出造血干细胞，例如多能干细胞，这些细胞能够在体内产生任何类型的细胞。这种方法为再生医学带来了巨大的希望，但目前在实验室中培养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基础性的重要性，但我们对造血干细胞是如何在胚胎发育期间首次出现的了解有限。我们最近的分析揭示了一个新的信号中心，Angpt2，我们发现它是小鼠胚胎中HSC出现的强烈刺激因素。我们观察到该因子在人类胚胎中的表达模式类似，表明它可能是一个重要的HSC调控中心，这在以前还没有被描述过。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、先进的成像、生物信息学和移植，对Ang2信号在推动胚胎HSC出现中的作用进行详细的研究。利用新的基于图像的空间相关方法，我们将在小鼠和人类胚胎HSC的发育中建立这个信号中心的第一个3D数字模型。这些3D模型和相关数据集将是该研究领域的宝贵资源。我们将进一步测试Angpt2是否能促进多能细胞产生造血细胞/HSC。从长远来看，这可能有助于制定在实验室生产造血干细胞的方案，以满足临床上造血干细胞的短缺。

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.