Simply Put
Adult tissue stem cells build and maintain all our tissues. Their regenerative capacity declines with age in ways that are still not well understood, especially in humans. Understanding how blood ages is of particular interest, because blood stem cells (or haematopoietic stem cells, HSCs) produce all blood cell types, including red blood cells which transport oxygen all over our bodies, platelets that prevent bleeding after injury, and immune cells, which not only protect us from bacteria and viruses, but also contribute to maintaining the integrity and function of most other tissues. The age-associated decline in blood stem cell function causes anaemia, failure to clear infections, poor vaccination responses, increased risk of blood cancers, and may also contribute to cardiovascular disease. In addition, recent work with animal models has shown that experimental approaches aimed at rejuvenating blood can improve the physiology of many aged organs. Characterising how blood ages is therefore an important priority towards extending the years we can live in good health.
Description
Proper blood formation can only be maintained by a diverse pool of HSCs and progenitor cells which collectively fine-tune blood production to meet the shifting demands of our bodies. The human HSC and progenitor compartment, also known as haematopoietic stem and progenitor cells (HSPCs), are phenotypically defined as cells expressing CD34 on their surface, or CD34+ cells.
In the pilot project, it was indicated how HSC and progenitor cell identities and proportions vary across the human lifespan. In the current project, this work will be extended to provide
1) Identity: Functional and molecular identity of aged blood stem cell and
2) Fitness: Estimation of blood stem cell fitness in older individuals (Figure 1).
The goal of this project is to investigate how the fitness of blood stem cells in any aged individual can be directly deduced from their molecular profiles. A high-resolution model will be produced of how human blood ages, incorporating epigenetics, transcriptomics, and genetics. Thus, an unprecedented resource will be generated, from which it will be possible to identify epigenetic and transcriptional signatures in combinations of acquired mutations that can be linked to specific health risk outcomes, including, but not limited to, blood cancers and cardiovascular disease. As blood cells contribute to the function of all tissues, the framework developed here will have implications for healthy ageing extending well beyond blood itself.
An in-depth study of the human HSC and progenitor compartment will be performed on the bone marrow of 5 young (<35 years old) and 5 older (>60 years old) adults in overall good health. The data generated from each approach will be fully integrated to generate a single cell resolution map of the ageing HSPC compartment, with genetic, epigenetic, transcriptional, and functional annotations (Figure 2). This proposal takes advantages of recent technological developments, which combine simultaneous measurements of 1) transcriptomes and cell surface proteins, 2) open chromatin and transcriptome, or 3) lineage tracing and transcriptome to capture how specific subsets of HSPCs produce blood cells with specific dynamics (which type of mature blood cells they preferentially produce, in which absolute numbers, proportions and with which kinetics). It will also allow the linking of the cellular output of each individual HSPC to its initial molecular state.
The final aim of the project is to link aged HSPC molecular and functional characteristics to somatic mutations unavoidably acquired with age. This aspect of the project will build upon work, co-led by Prof. Laurenti, showing that mutations arising in stem cells over time can be used to track their life-history, including, for example, to determine if specific stem cells acquired a competitive advantage over others leading them to dominate blood production. Using this method, Prof. Laurenti’s team showed that genetic diversity of the human HSPC pool drastically declines past the age of 70. This phenomenon of “oligoclonality”, particularly when driven by specific mutations, is linked to increased risks not only of blood cancer but also of cardiovascular disease and other chronic inflammatory conditions typical of the elderly. This work partly explains why ageing characteristics are so different between individuals, since we all acquire mutations which will affect our stem cell function, but which mutations we acquire will vary between individuals, making each of us more or less at risk of disease. It is therefore important to delineate how specific genetic mutations, which are selected in most of us over time, affect HSC molecular profiles and their capacity to produce blood.
Recently, ~ 900 mutations were uncovered in genes or regulatory genomic regions that provide HSCs with a competitive advantage over time. HSCs carrying these mutations will come to predominate the blood system with age. By the age of 70, 30-60% of all our mature blood cells will be produced by only 10-20 HSCs carrying these mutations (in contrast to ~ 100,000 HSCs in youth).
This methodology would enable for the first time to link specific transcriptional states of HSCs to specific mutations determining clonal expansion.
Results
The project’s start date is October 1, 2023.