Tracking the embryonic origin of the adult haematopoietic system

追踪成人造血系统的胚胎起源

基本信息

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

项目摘要

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.

当接受化学疗法或放疗的患者接受骨髓移植时，它包括血管细胞，也称为造血干细胞（HSC），这是正常血液的长期来源。但是，骨髓和脐带移植缺乏，在实验室条件下产生HSC存在主要兴趣。尽管HSC在胚胎发育过程中发展，但尚不清楚如何在培养的细胞中重现这一过程。为了了解胚胎用于生成HSC的机制，研究人员需要首先追踪其起源于胚胎并跟踪其发育，这是一个令人惊讶的理解过程。早期胚胎中的第一个血细胞在一个称为蛋黄囊的膜外发育。但是，可以在成年动物中持续存在的真正HSC出现在发育中的胚胎的特定部分。该研究建议的主要目的是确定成人HSC的确切起源部位。小鸡胚胎对这项研究非常有用，因为我们可以在菜肴或鸡蛋中看到它的发育，而不会破坏正常发育。为此，我们开发了新工具 - 表达荧光蛋白的转基因鸡，因此可以在显微镜下的活胚胎中轻松遵循其细胞。通过从怀疑将HSC祖先寄生到正常鸡肉胚胎的区域的精确转基因雏鸡胚胎组织碎片移植，我们将监测它们是否发展为血液。这将使我们能够定义HSC发展的胚胎细胞的确切位置。新型的转基因雏鸡菌株，其中特定细胞类型被不同的荧光报告蛋白标记，将进一步定义HSC胚胎祖先的更精确定位。这些新工具的开发将使我们有一个独特的机会来识别和表征HSC。从较长的角度来看，这些知识将为您从胚胎干细胞生成HSC的方法的发展，用于治疗由于化学或放射疗法而导致血液形成受损的患者。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
期刊：
影响因子：
0
作者：
Jackson M
通讯作者：
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

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

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
影响因子：
0
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

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Alexander Medvinsky其他文献

Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

DOI：
10.1182/blood-2015-09-669036
发表时间：
2016-04-14
期刊：
Short communication
影响因子：
作者：
Cristina Mirantes;Maria Alba Dosil;David Hills;Jian Yang;Núria Eritja;Maria Santacana;Sònia Gatius;Felip Vilardell;Alexander Medvinsky;Xavier Matias-Guiu;Xavier Dolcet
通讯作者：
Xavier Dolcet

3074 – SINGLE CELL TRANSCRIPTOMIC ANALYSIS COMBINED WITH MACHINE LEARNING IDENTIFIES HSC-LIKE CELLS DIFFERENTIATED IN VITRO FROM HUMAN IPSCS.

DOI：
10.1016/j.exphem.2020.09.090
发表时间：
2020-08-01
期刊：
Conference abstract
影响因子：
作者：
Antonella Fidanza;Patrick Stumpf;Prakash Ramachandran;Helen Taylor;Sara Tamagno;Ann Babtie;Alexander Medvinsky;Katrin Ottersbach;Nicola Romano;Lesley Forrester
通讯作者：
Lesley Forrester

Investigating haematopoiesis in the human embryo using an ex vivo culture system

DOI：
10.1016/j.exphem.2016.06.122
发表时间：
2016-09-01
期刊：
Conference abstract
影响因子：
作者：
Jennifer Easterbrook;Sabrina Gordon-Keylock;Stanislav Rybtsov;Andrejs Ivanovs;Richard Anderson;Alexander Medvinsky
通讯作者：
Alexander Medvinsky

Analysis of notch signalling activity during hematopoietic stem cell development

DOI：
10.1016/j.exphem.2015.06.131
发表时间：
2015-09-01
期刊：
Conference abstract
影响因子：
作者：
Javier Gonzalez;Javier G. Lendinez;Celine Souilhol;Stanislav Rybtsov;David Hills;Suling Zhao;Alexander Medvinsky
通讯作者：
Alexander Medvinsky

3004 – IDENTIFICATION AND CHARACTERIZATION OF NOVEL FUNCTIONAL MARKERS DURING THE HEMATOPOIETIC STEM CELL SPECIFICATION PROCESS

DOI：
10.1016/j.exphem.2020.09.026
发表时间：
2020-08-01
期刊：
Conference abstract
影响因子：
作者：
Marleen Büchler-Schäff;Paul Kaschutnig;Roshana Thambyrajah;Wiebke Nadler;Sabrina Hanke;Stella Pfaffenholz;Milena Block;Julius Gräsel;Jakob Kremer;Irem Bayindir-Buchhalter;Wenjun Chang;David Hills;Richard Harbottle;Chrisoph Rösli;Alexander Medvinsky;Michéle Souyri;Georges Lacaud;Michael Milsom
通讯作者：
Michael Milsom