TACKLING FUNCTIONAL MATURATION FOR TRANSPLANTABLE HEMATOPOIETIC STEM CELL GENERATION

Project Information

FUN-HSC

Grant agreement ID: 101088313

DOI

10.3030/101088313

EC signature date 15 November 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 265 684,00

EU contribution

€ 2 265 684,00

Coordinated by

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS
Spain

Periodic Reporting for period 1 - FUN-HSC (TACKLING FUNCTIONAL MATURATION FOR TRANSPLANTABLE HEMATOPOIETIC STEM CELL GENERATION)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Blood stem cells are special cells in our body that produce all blood and immune cells throughout life. They are already used in life-saving treatments for leukemia, and their use is expanding to gene and cell therapies aimed at treating other cancers, genetic diseases, autoimmune disorders, and infections. However, these therapies are not available to many patients because suitable donors cannot always be found, and sometimes the number of stem cells available is too low. Attempts to overcome these limitations by creating blood stem cells in the laboratory from pluripotent stem cells led to generation of cells that look like blood stem cells, but that behave more like immature cells from early development and lack the full functionality needed for effective treatment. The FUN-HSC project aims to understand how blood stem cells mature during human development and to identify the key biological pathways that control this process.
During fetal development, blood stem cells mature in the liver, where they acquire the ability to produce all types of blood cells throughout life. By studying human embryonic and fetal tissues at single-cell resolution, we have identified several gene programs that change as blood stem cells mature. Building on this knowledge, the project will investigate how developing stem cells interact with their surrounding environment in the fetal liver. Using new laboratory models that recreate this environment, such as organoids and mouse transplantation models, we will test which signals are necessary for stem cell maturation. Ultimately, the goal is to reproduce these developmental signals in the laboratory so that stem cells created from pluripotent stem cells can mature into fully functional blood stem cells. By combining new insights into human blood stem cell biology with advanced genetic and tissue-engineering technologies, FUN-HSC aims to bring us closer to producing reliable blood stem cells for therapy, expanding their life-saving potential for many more patients.

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

Important progress has already been made towards the FUN-HSC objectives, and several key achievements are laying the foundation for major scientific results in the next phases of the project:
• We have generated the first comprehensive molecular map describing how blood stem cells mature in the human fetal liver and fetal bone marrow.
• We have identified key gene-regulatory mechanisms that appear to control when blood stem cells acquire the ability to successfully engraft and function after transplantation.
• We are investigating functional differences between blood stem cells developing in different environments (the fetal liver versus the fetal bone marrow), including their ability to produce different blood cell types, their energy metabolism, protein production, and their capacity to engraft in living models.
• We have created new stem cell engineering platforms using CRISPR technology that will allow large-scale screening of genes involved in blood stem cell maturation.
Together, these advances establish the experimental tools, datasets, and model systems necessary to achieve the project’s main objective: understanding how blood stem cells mature and applying this knowledge to generate fully functional blood stem cells in the laboratory.

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)

The FUN-HSC project is generating new knowledge and technologies that will significantly advance stem cell biology and regenerative medicine. Blood stem cells are used in life-saving transplants for leukemia and other blood diseases, but their availability is limited because compatible donors cannot always be found and existing sources often provide too few cells. A long-standing goal in the field is therefore to produce fully functional blood stem cells in the laboratory. FUN-HSC aims to contribute to this objective by uncovering the biological mechanisms that allow these cells to mature and become capable of long-term blood production after transplantation.
A key outcome of the project is the generation of a comprehensive molecular map describing how human blood stem cells mature during fetal development. This knowledge provides an essential foundation for developing strategies to reproduce these maturation processes in vitro. In parallel, FUN-HSC is developing innovative experimental platforms that combine induced pluripotent stem cells with CRISPR-based genome engineering. These systems will enable large-scale functional testing of genes and regulatory DNA elements that control stem cell maturation, providing powerful tools for both this project and the wider research community.
To ensure the future uptake of these results, further research will focus on validating the identified pathways and translating them into robust laboratory protocols capable of generating functional blood stem cells. Broad dissemination of datasets, engineered cell lines, and experimental methods will help accelerate progress across the international research community.
By the end of the project, FUN-HSC is expected to deliver a detailed atlas of human blood stem cell maturation, new platforms for functional genomic screening, and candidate strategies to generate transplantable blood stem cells. These outcomes will provide both fundamental biological insight and practical tools to support future advances in stem-cell-based therapies.