Tracking the embryonic origin of the adult haematopoietic system

追踪成人造血系统的胚胎起源

• 批准号: MR/L018160/1
• 负责人: Alexander Medvinsky
• 金额: $ 101.23万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018160%2F1
• 关键词: Tracking; embryonic; origin; adult; haematopoietic

When a patient who has undergone chemotherapy or radiotherapy receives a bone marrow transplant, it includes blood stem cells also known as haematopoietic stem cells (HSCs) which are the long-term source of normal blood. However, there is a shortage of bone marrow and umbilical cord transplants and there is a major interest to generate HSCs in the laboratory conditions. Although HSCs develop during embryo development, it is not yet clear how to reproduce this process in cultured cells. To understand mechanisms that the embryo uses to generate HSCs, researchers need to first trace their origin in the embryo and track their development, which is a surprisingly poorly understood process. The first blood cells in the early embryo develop outside its body in a membrane called the yolk sac. However, true HSCs which can persist in the adult animal appear later in a specific part of the developing embryo. The main objective of this research proposal is to identify the precise site of origin of adult HSCs. The chick embryo is very useful for this research as we can see its development in a dish or in the egg, without disrupting normal development. To this end we have developed new tools - transgenic chickens that express fluorescent proteins, so that their cells can be easily followed in live embryos under the microscope. By transplantation of precise transgenic chick embryonic tissue fragments from regions suspected to harbour the ancestors of HSCs into normal chicken embryos we will monitor whether they develop into blood. This will allow us to define the exact location of embryonic cells from which HSCs develop. Novel transgenic chick strains where particular cell types are labelled by different fluorescent reporter proteins will further define more precise localisation of embryonic ancestors of HSCs. The development of these new tools will give us a unique opportunity to identify and characterise HSCs. In the longer terms, this knowledge will inform the development of methods for generation of HSCs from embryonic stem cells for treatment of patients whose blood formation was impaired due to chemo- or radiotherapy.

当接受化疗或放疗的患者接受骨髓移植时，它包括血液干细胞，也称为造血干细胞（HSC），是正常血液的长期来源。然而，骨髓和脐带移植物短缺，并且在实验室条件下产生HSC具有重大意义。尽管HSC在胚胎发育过程中发育，但目前尚不清楚如何在培养细胞中重现这一过程。为了了解胚胎用于产生HSC的机制，研究人员需要首先追踪它们在胚胎中的起源并跟踪它们的发育，这是一个令人惊讶的知之甚少的过程。早期胚胎中的第一个血细胞在体外发育，形成一层叫做卵黄囊的膜。然而，可以在成年动物中持续存在的真正的HSC稍后出现在发育胚胎的特定部分。这项研究的主要目的是确定成年HSC的确切起源部位。鸡胚对这项研究非常有用，因为我们可以看到它在培养皿或鸡蛋中的发育，而不会破坏正常发育。为此，我们开发了新的工具-表达荧光蛋白的转基因鸡，这样它们的细胞就可以在显微镜下很容易地在活胚胎中进行跟踪。通过移植精确的转基因鸡胚胎组织片段，从区域怀疑窝藏HSC的祖先到正常的鸡胚胎，我们将监测他们是否发育成血液。这将使我们能够确定HSC发育的胚胎细胞的确切位置。新的转基因鸡株，其中特定的细胞类型被不同的荧光报告蛋白标记，将进一步定义更精确的定位胚胎祖先的HSC。这些新工具的开发将为我们提供一个独特的机会来识别和识别HSC。从长远来看，这些知识将为开发从胚胎干细胞产生HSC的方法提供信息，用于治疗由于化疗或放疗而导致血液形成受损的患者。

项目成果

Modulation of Aplnr signaling is required during the development and maintenance of the hematopoietic system

造血系统的发育和维持过程中需要调节 Aplnr 信号

• DOI: 10.1101/2020.06.15.145649
• 发表时间: 2020
• 作者: Jackson M

Vast Self-Renewal Potential of Human AGM Region HSCs Dramatically Declines in the Umbilical Cord Blood.

• DOI: 10.1016/j.stemcr.2020.08.008
• 发表时间: 2020-10-13
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Ivanovs A;Rybtsov S;Anderson RA;Medvinsky A
• 通讯作者: Medvinsky A

A molecular roadmap of the AGM region reveals BMPER as a novel regulator of HSC maturation.

• DOI: 10.1084/jem.20162012
• 发表时间: 2017-12-04
• 期刊: The Journal of experimental medicine
• 作者: McGarvey AC;Rybtsov S;Souilhol C;Tamagno S;Rice R;Hills D;Godwin D;Rice D;Tomlinson SR;Medvinsky A
• 通讯作者: Medvinsky A

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