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

胚胎造血干细胞生态位中新型血管生成素 2 信号中心的鉴定

• 批准号: MR/R018081/1
• 负责人: Alexander Medvinsky
• 金额: $ 80.62万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR018081%2F1
• 关键词: IDENTIFICATION; NOVEL; ANGIOPOIETIN; SIGNALLING; CENTRE

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.

造血干细胞（HSCs）是造血干细胞的一种，是造血干细胞的一种，是造血干细胞的一种。多年来，HSC移植已被用于（全球约50，000例患者/年）恢复血液疾病和癌症患者的正常血液形成。然而，捐献者严重短缺，登记在册的患者中只有20-60%找到了移植的良好遗传匹配，这影响了治疗选择、效率和结果。因此，迫切需要找到HSC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产生HSC，例如多能干细胞，其能够在体内产生任何细胞类型。这种方法为再生医学带来了巨大的希望，但目前在实验室中产生HSC仍然是一个巨大的挑战，主要是因为，尽管对医学科学具有根本的重要性，但我们对HSC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个新的信号中心，Angpt 2，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，这表明它可能是一个重要的HSC调控中心，这在以前没有描述过。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Ang 2信号在驱动胚胎HSC出现中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，我们将建立这个信号中心在小鼠和人类胚胎HSC发育的第一个3D数字模型。这些3D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Angpt 2是否可以增强从多能细胞产生造血细胞/ HSC。从长远来看，这可能有助于开发在实验室中生产HSC的方案，以满足临床上HSC的短缺。

项目成果

Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development.

• DOI: 10.1016/j.stem.2020.08.004
• 发表时间: 2020-11-05
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Crosse EI;Gordon-Keylock S;Rybtsov S;Binagui-Casas A;Felchle H;Nnadi NC;Kirschner K;Chandra T;Tamagno S;Webb DJ;Rossi F;Anderson RA;Medvinsky A
• 通讯作者: Medvinsky A