Cellular and molecular dynamics of healthy ageing in the human Haematopoietic Stem Cell compartment

人类造血干细胞室健康衰老的细胞和分子动力学

• 批准号: BB/P002293/1
• 负责人: Elisa Laurenti
• 金额: $ 68.14万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP002293%2F1
• 关键词: Cellular; molecular; dynamics; healthy; ageing

Blood comprises more than a dozen distinct cell types which have vital functions and are constantly replaced, at a rate of 30 millions cells per minute in humans. This extreme regenerative capacity can be maintained thanks to haematopoietic stem cells (HSC), rare cells that have the unique ability to produce more of themselves as well as all blood cell types. Interestingly there isn't a single type of HSC but rather HSC come in different flavours (subtypes), which vary in their capacity to divide and have preferences for production of particular differentiated blood cell types. Importantly it is thanks to this heterogeneity in the HSC compartment that blood production can be maintained under normal conditions or after injury or infection. The unique potential of HSC is exploited in bone marrow transplantation, a procedure routinely used in the clinic to treat leukaemia and other conditions. HSC are harvested from different haematopoietic organs depending on the clinical case. There is evidence that the source of HSC can affect the outcome of the transplantation, but why is not currently understood. In addition, work with animal models has demonstrated that HSC function is compromised with age. Correspondingly, in elderly people there are many changes in the composition of the blood and an increased incidence of infections, anaemia and blood cancers. However despite their importance for human health and for treatment, almost nothing is known to date on the composition of the human HSC compartment in different organs, how it changes with ageing, and what are the consequences for blood production. This project will use a number of innovative single cell analysis techniques and computational methods to compare the composition of the healthy human HSC compartment in different haematopoietic organs: neonatal cord blood as well as adult bone marrow, peripheral blood and spleen. For each organ we will define how many HSC subsets there are, and identify their gene expression profiles, epigenetic features and functional properties. We will also determine how these change with healthy ageing by analysing samples ranging from infants to 70 years old individuals. Single cell resolution is absolutely necessary to understand how HSC age. The information derived from this comprehensive study will characterise how human HSC, and consequently blood production, change over a lifetime. Our molecular characterisation will also provide a resource to develop new strategies to improve current transplantation protocols and to identify targets that may help to pharmacologically rejuvenate old HSC and correct some of the age-related blood deficiencies.

血液由十几种不同的细胞组成，它们具有重要的功能，并以每分钟3000万个细胞的速度不断更新。这种极端的再生能力可以保持感谢造血干细胞（HSC），罕见的细胞，具有独特的能力，以产生更多的自己以及所有血细胞类型。有趣的是，没有单一类型的HSC，而是HSC有不同的风味（亚型），它们的分裂能力不同，并且对特定分化的血细胞类型的产生有偏好。重要的是，由于HSC隔室中的这种异质性，血液生产可以在正常条件下或损伤或感染后维持。造血干细胞的独特潜力被用于骨髓移植，这是一种在临床上常规用于治疗白血病和其他疾病的程序。HSC根据临床情况从不同的造血器官收获。有证据表明，HSC的来源可以影响移植的结果，但为什么目前还不清楚。此外，动物模型的研究表明，HSC的功能随着年龄的增长而受损。相应地，老年人的血液成分发生了许多变化，感染、贫血和血癌的发病率也增加了。然而，尽管它们对人类健康和治疗很重要，但迄今为止，人们对不同器官中人类HSC区室的组成、它如何随着衰老而变化以及对血液产生的影响几乎一无所知。该项目将使用许多创新的单细胞分析技术和计算方法来比较不同造血器官中健康人类HSC区室的组成：新生儿脐带血以及成人骨髓，外周血和脾脏。对于每个器官，我们将定义有多少HSC亚群，并确定其基因表达谱，表观遗传特征和功能特性。我们还将通过分析从婴儿到70岁老人的样本来确定这些变化与健康老龄化的关系。单细胞分辨率对于理解HSC如何老化是绝对必要的。从这项综合研究中获得的信息将揭示人类HSC以及因此产生的血液生产在一生中如何变化。我们的分子表征还将提供资源，以开发新的策略，以改善当前的移植方案，并确定可能有助于使老年HSC恢复活力和纠正一些与年龄相关的血液缺陷的靶点。

项目成果

Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome

• DOI: 10.1101/2021.06.25.449771
• 发表时间: 2021-06
• 期刊: bioRxiv
• 作者: Laura Jardine;S. Webb;Issac Goh;Mariana Quiroga Londoño;G. Reynolds;M. Mather;B. Olabi;Emily Stephenson;R. Botting;D. Horsfall;J. Engelbert;Daniel Maunder;N. Mende;Caitlin Murnane;Emma Dann;J. McGrath;Hamish W. King;I. Kucinski;R. Queen;Christopher D. Carey;C. Shrubsole;Elizabeth Poyner;M. Acres;Claire Jones;T. Ness;Rowan Coulthard;N. Elliott;Sorcha O’Byrne;M. Haltalli;Johnathan E. Lawrence;S. Lisgo;P. Balogh;K. Meyer;E. Prigmore;K. Ambridge;M. S. Jain;M. Efremova;K. Pickard;T. Creasey;J. Bacardit;D. Henderson;J. Coxhead;A. Filby;Rafiqul Hussain;D. Dixon;David McDonald;Dorin-Mirel Popescu;Monika S. Kowalczyk;Bo Li-;Orr Ashenberg;M. Tabaka;Danielle Dionne;Timothy L. Tickle;M. Slyper;O. Rozenblatt-Rosen;A. Regev;S. Behjati;E. Laurenti;Nicola K. Wilson;A. Roy;B. Göttgens;I. Roberts;S. Teichmann;M. Haniffa

Blood and immune development in human fetal bone marrow and Down syndrome.

人类胎儿骨髓和唐氏综合症的血液和免疫发育。

• DOI: 10.17863/cam.76568
• 发表时间: 2021
• 作者: Jardine L

From haematopoietic stem cells to complex differentiation landscapes.

• DOI: 10.1038/nature25022
• 发表时间: 2018-01-24
• 期刊: Nature
• 影响因子: 64.8
• 作者: Laurenti E;Göttgens B
• 通讯作者: Göttgens B

Myelo-lymphoid lineage restriction occurs in the human haematopoietic stem cell compartment before lymphoid-primed multipotent progenitors.

• DOI: 10.1038/s41467-018-06442-4
• 发表时间: 2018-10-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Belluschi S;Calderbank EF;Ciaurro V;Pijuan-Sala B;Santoro A;Mende N;Diamanti E;Sham KYC;Wang X;Lau WWY;Jawaid W;Göttgens B;Laurenti E
• 通讯作者: Laurenti E