Transcriptional and epigenetic mechanisms of HSC subtype diversification

HSC亚型多样化的转录和表观遗传机制

• 批准号: BB/V002198/1
• 负责人: Claus Nerlov
• 金额: $ 58.89万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV002198%2F1
• 关键词: Transcriptional; epigenetic; mechanisms; HSC; subtype

The blood cells in the human body perform various tasks, including blood clotting, oxygen supply and diverse immune responses. A rare population of hematopoietic stem cells (HSCs) can produce all blood cells. During ageing, the ability of HSCs to generate blood cells significantly declines. They produce less red blood cells that transport oxygen and less immune cells that fight against infections, which are the potential causes of ageing-associate anaemia, immune deficiency and blood cancers. Yet, it is not clear how these changes of HSCs occur during ageing. In this project we aim to identify critical molecules that are controlling the blood cell production of HSCs. We have developed a technique that allows us to measure the blood cell production of a single HSC, and found that there are different types of HSCs with vastly different ability to make different types of blood cells. We now wish to examine if changes to the abundance of the different HSC subtypes can account for the declined production of red cells and immune cells in aged people. The aim of these studies is to identify key molecules that have influences on HSCs, and by targeting these molecules to prevent or ultimately revert the decline in blood cell production in aged people.

人体内的血细胞执行各种任务，包括凝血、供氧和多种免疫反应。罕见的造血干细胞 (HSC) 群体可以产生所有血细胞。在衰老过程中，造血干细胞生成血细胞的能力显着下降。它们产生的输送氧气的红细胞和抵抗感染的免疫细胞较少，而感染是衰老相关贫血、免疫缺陷和血癌的潜在原因。然而，目前尚不清楚造血干细胞在衰老过程中如何发生这些变化。在这个项目中，我们的目标是识别控制 HSC 血细胞生成的关键分子。我们开发了一种技术，可以测量单个 HSC 的血细胞生成量，并发现不同类型的 HSC 生成不同类型血细胞的能力差异很大。我们现在希望研究不同 HSC 亚型丰度的变化是否可以解释老年人红细胞和免疫细胞产量的下降。这些研究的目的是确定影响造血干细胞的关键分子，并通过靶向这些分子来预防或最终逆转老年人血细胞生成的下降。

项目成果

Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion.

• DOI: 10.1186/s13059-023-02976-z
• 发表时间: 2023-06-27
• 期刊: Genome biology
• 影响因子: 12.3

Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner.

• DOI: 10.1038/s41467-023-41691-y
• 发表时间: 2023-09-28
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Luis, Tiago C.;Barkas, Nikolaos;Carrelha, Joana;Giustacchini, Alice;Mazzi, Stefania;Norfo, Ruggiero;Wu, Bishan;Aliouat, Affaf;Guerrero, Jose A.;Rodriguez-Meira, Alba;Bouriez-Jones, Tiphaine;Macaulay, Iain C.;Jasztal, Maria;Zhu, Guangheng;Ni, Heyu;Robson, Matthew J.;Blakely, Randy D.;Mead, Adam J.;Nerlov, Claus;Ghevaert, Cedric;Jacobsen, Sten Eirik W.
• 通讯作者: Jacobsen, Sten Eirik W.

DNMT1 Deficiency Impacts on Plasmacytoid Dendritic Cells in Homeostasis and Autoimmune Disease.

• DOI: 10.4049/jimmunol.2100624
• 发表时间: 2022-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Czeh M;Stäble S;Krämer S;Tepe L;Talyan S;Carrelha J;Meng Y;Heitplatz B;Schwabenland M;Milsom MD;Plass C;Prinz M;Schlesner M;Andrade-Navarro MA;Nerlov C;Jacobsen SEW;Lipka DB;Rosenbauer F
• 通讯作者: Rosenbauer F