What does your blood remember? The memory of hematopoietic stem cells.

Project Information

StemMemo

Grant agreement ID: 101041737

DOI

10.3030/101041737

EC signature date 12 April 2022

Start date 1 June 2022

End date 31 May 2027

Funded under

• European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

UNIWERSYTET JAGIELLONSKI
Poland

Periodic Reporting for period 1 - StemMemo (What does your blood remember? The memory of hematopoietic stem cells.)

Reporting period: 2022-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

Hematopoietic stem cells (HSCs) are the foundational cells responsible for producing all blood cells throughout our lives. It is estimated that one million new blood cells are generated every second in our bodies. This dynamic and complex system must be meticulously regulated to maintain homeostasis and to respond swiftly to increased demands, such as during infections or chronic bleeding.

The aim of our project is to understand how the hematopoietic system reacts to repetitive challenges. Specifically, we want to investigate whether hematopoietic stem cells can "remember" the challenges they encounter and leverage this potential memory to produce the necessary blood cells more efficiently upon subsequent demands. Traditionally, the concept of memory in blood cells has been linked to adaptive immunity, involving B and T cells that can remember the antigens of encountered pathogens, which forms the basis of vaccination. However, in this project, we are exploring the memory of the hematopoietic system beyond lymphocytes and adaptive immunity.

Hematopoietic stem cells are crucial for the long-term regenerative potential of bone marrow and mobilized peripheral blood transplants. We believe that understanding how these cells react to hematopoietic challenges and how these challenges shape the function of HSCs over the long term may be vital for enhancing their efficacy in clinical transplantations. For instance, if HSCs can be conditioned to remember and respond more effectively to recurrent demands, this could significantly improve outcomes for patients undergoing bone marrow transplants.

Moreover, an aberrant memory of HSCs might contribute to blood disorders, highlighting the broader significance of this project. By delving into the mechanisms of HSC memory, we aim to uncover new therapeutic strategies to enhance blood production in patients with various hematological conditions and improve the overall success rates of stem cell transplants.

In summary, our project seeks to unlock the potential of hematopoietic stem cell memory, providing insights that could revolutionize how we approach the treatment of blood-related diseases and improve the effectiveness of stem cell therapies. This research not only deepens our understanding of stem cell biology but also paves the way for innovative clinical applications that could benefit countless patients in the future.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To investigate how hematopoietic stem cells (HSCs) respond to challenges and understand their long-term impact, we conducted our research using mouse models. We stimulated hematopoiesis (the process of forming blood cells) with specific cytokines—signaling proteins that trigger the production of particular types of blood cells. By doing so, we monitored how this stimulation reprograms hematopoiesis and observed when and how the system returns to homeostasis (a balanced state).
A crucial element of our research is studying HSCs at the single-cell level. We isolated individual hematopoietic stem cells from mice and cultured each one separately to observe how quickly it produces blood cells and the types of blood cells that emerge from a single stem cell. To achieve this, we developed a specialized, advanced system based on automated microscopy. This system tracks the initial division of stem cells and their differentiation into mature blood cells. Additionally, we monitored differences in gene expression between young and old HSCs, providing insights into how aging affects stem cell function.
In the second part of our experiments, we isolated highly purified hematopoietic stem cells from mice and transplanted them into other mice to verify their regenerative potential and the types of blood cells they preferentially produce. These transplantation experiments allowed us to assess the functionality and adaptability of HSCs in a new environment.
Our experiments revealed that hematopoiesis can adapt rapidly to hematopoietic challenges. However, in long-term perspective, stimulating the production of a specific blood cell lineage leaves a functional mark on the stem cell population.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our research has uncovered potentially significant findings about certain factors that stimulate blood cell production and can have long-term effects on the blood formation process. We observed that repeated stimulation with these treatments leads to temporary decreases in specific types of blood cell precursors and may causes fluctuations in the counts of different kinds of blood cells. We show also how the hematopoietic stem cells change with age.
While the observed effects are minor and clinically acceptable in contrast to acute stress conditions, our findings suggest that even mild temporary disturbances in blood cell production might have important clinical implications. It’s crucial to understand these effects better, especially since some of such treatments are commonly used to help patients.
However, it's important to note that our current results are based on mouse models, and we don't yet fully understand the exact mechanisms behind these effects. While we believe these findings could be very important, more research is needed to uncover how these treatments influence blood stem cells and their offspring over the long term. This involves studying the recovery process of blood formation in great detail to understand how different hematopoietic stimuli reprogram hematopoiesis in long-term perspective.
These findings may be significant because they provide new insights into how blood cell production can be regulated and optimized. Understanding the memory and adaptability of hematopoietic stem cells could lead to improved treatments for various blood disorders and enhance the success rates of stem cell transplants. By uncovering the mechanisms behind stem cell memory, our research paves the way for developing innovative therapeutic strategies that could benefit patients with hematological conditions, ultimately contributing to better health outcomes and advancements in regenerative medicine.

Scientific topic of the grant