Dissecting the molecular regulation of hematopoietic stem cell emergence using pluripotent stem cells to improve ex vivo therapies

Informations projet

HSC-reNEW

N° de convention de subvention: 101044032

DOI

10.3030/101044032

Date de signature de la CE 15 Decembre 2022

Date de début 1 Mars 2023

Date de fin 29 Février 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 2 000 000,00

Contribution de l’UE

€ 2 000 000,00

Coordonné par

OSPEDALE SAN RAFFAELE SRL
Italy

Periodic Reporting for period 1 - HSC-reNEW (Dissecting the molecular regulation of hematopoietic stem cell emergence using pluripotent stem cells to improve ex vivo therapies)

Période du rapport: 2023-03-01 au 2025-08-31

Résumé du contexte et des objectifs généraux du projet

Hematopoietic stem cells (HSCs) are responsible for producing all blood and immune cells in the body and have been used for decades to treat diseases such as leukemia and other blood disorders. However, a major limitation of this therapy is the scarcity of compatible donors and the difficulty in expanding HSCs outside the body. Our project, HSC-reNEW, aims to tackle this challenge by understanding how these stem cells naturally develop in the human embryo, with the ultimate goal of reproducing that process in the lab.
To achieve this, we study human pluripotent stem cells (hPSCs)—a type of cell that can develop into any tissue in the body—as a model for how blood cells are formed during early development. By decoding the principle guiding these stem cells to become blood-forming HSCs, we aim to produce transplantable blood stem cells entirely in the lab. If successful, this would remove the dependence on donors, providing a renewable and patient-specific source of stem cells. In addition, we will activate the same principle in existing primary HSCs in the attempt to expand them - an approach that could dramatically improve outcomes and reduce risks associated with transplants.
Our research tackles three main questions:
1. How do blood cells first emerge during development?
2. Can we recreate this process to make real HSCs from hPSCs?
3. Can we expand adult HSCs in the lab to treat more patients?
The answers to these questions could revolutionize how we treat genetic blood diseases, childhood bone marrow failure syndromes, and leukemia. As such, through this work, HSC-reNEW is positioned to address a critical unmet need in medicine, opening the door to safer, more accessible, and more personalized treatments for a range of life-threatening diseases.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Over the course of the project, we have made key discoveries that are moving us closer to generating hematopoietic stem cells in the lab. First, we identified a surface marker (CD32) that can isolate cells that are definitively committed to becoming blood cells. This breakthrough allowed us to better track and study the early stages of blood cell development both in the lab and in human embryos.
By analyzing gene activity in these cells, we found that specific proteins active during a process known as post-transcriptional regulation—where the cell fine-tunes gene expression after the initial instructions are read—are crucial for blood cell emergence. These findings offer a new angle on how the blood program is switched on during development.
We also developed new culture conditions that significantly improve the yield of blood progenitors from hPSCs, in particular of cells displaying enhanced self-renewal, a defining feature of true HSCs. These new conditions enhance the generation and long-term function of lab-grown blood stem cells.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The outcomes of HSC-reNEW have advanced the field of stem cell and regenerative medicine in multiple ways. Scientifically, we challenged and revised a longstanding belief about how blood cells originate in the embryo. Our data suggest that blood-producing cells do not emerge from typical endothelial (vessel-lining) cells, but instead from a transient, blood-specific population—reshaping how scientists understand blood development.
Technologically, our refined method for producing blood cells in a dish—combined with a patented marker (CD32) and new culture media—offers a blueprint for creating transplant-ready blood cells without relying on donors.
Functionally, we are decoding the master regulators of blood cell emergence and of self-renewal in blood stem cells. Of note, the latter may also play a role in aggressive leukemias. Through these efforts, we are beginning to produce more durable and potent blood stem cells. This opens up not only clinical avenues for treating blood disorders but also new insights into cancer biology.
Looking ahead, the project is laying the foundation for commercialization through patent filings and early discussions with biotech partners. With further validation, these advances could lead to clinical trials offering regenerative therapies to patients who currently have limited or no options.

Overarching goal