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

血液由十几种不同的细胞组成，这些细胞具有重要的功能，并不断被替换，人类每分钟有3000万个细胞被替换。由于造血干细胞（HSC），这种罕见的细胞具有独特的能力，可以产生更多的自身和所有类型的血细胞，这种极端的再生能力可以保持。有趣的是，没有单一类型的造血干细胞，而是有不同的口味（亚型），它们的分裂能力各不相同，并倾向于产生特定的分化血细胞类型。重要的是，正是由于造血细胞间室的这种异质性，造血才能在正常情况下或损伤或感染后保持。造血干细胞的独特潜力被用于骨髓移植，这是临床治疗白血病和其他疾病的常规方法。根据临床情况，从不同的造血器官中采集造血干细胞。有证据表明，HSC的来源可以影响移植的结果，但目前尚不清楚其中的原因。此外，动物模型的研究表明，HSC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增加。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室的组成、它如何随着年龄的增长而变化以及对血液产生的影响几乎一无所知。该项目将使用一些创新的单细胞分析技术和计算方法来比较不同造血器官（新生儿脐带血以及成人骨髓、外周血和脾脏）中健康人HSC室的组成。对于每个器官，我们将定义有多少HSC亚群，并确定它们的基因表达谱，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，确定这些因素如何随着健康老龄化而变化。单细胞分辨率对于了解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描述人类HSC和血液生产在一生中是如何变化的。我们的分子特征也将为开发新策略提供资源，以改进当前的移植方案，并确定可能有助于从药理学上恢复旧HSC和纠正一些与年龄相关的血液缺陷的靶标。

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.