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05/06/2024 - Press release

Researchers discover a protein’s function that can open the door to the generation of blood stem cells in the laboratory to treat leukaemia and other diseases

• A scientific team led by Dr Anna Bigas, from the Hospital del Mar Research Institute and the Josep Carreras Institute, has described the role of the IκBα protein in the differentiation process of haematopoietic cells.
• In the absence of this protein, the stem cells enter quiescence, acquire a dormant state and maintain their potential, which may allow them to be transplanted for therapeutic uses in leukaemia or blood diseases of genetic origin.
• This is an important step towards being able to generate these types of cells in the lab, preventing them from differentiating and turning into other cells too early.

Better tools for generating haematopoietic stem cells in the laboratory - the cells responsible for the generation and renewal of blood and the immune system, may open the door to new treatments for leukaemia or genetic blood diseases. These cells could be generated and transplanted into the patient, so they can develop into new cells and thus regenerate the blood. This is currently not possible, as they quickly differentiate and cease to have the properties that make them stem cells. However, a recent study published in the journal Nature Communications may change this. The study has been signed by researchers from the Hospital de Mar Research Institute, the Josep Carreras Leukaemia Research Institute, and the CIBER Cancer Research Centre (CIBERONC), and it was led by Dr. Anna Bigas.

The work has focused on the role of a protein, IκBα, which is involved in the regulation of inflammation, but also in that of genes related to stem cells in tissues. To test its activity in blood, its role has been studied from mouse embryos that had been modified to eliminate this protein. This allowed the researchers to analyze how the absence of IκBα influenced the ability of hematopoietic stem cells to develop into mature blood cells or to remain in their initial state.

The study has shown that the number of hematopoietic stem cells generated in these IκBα-deficient embryos is scarce, but, despite this, these cells maintain their stem cell potential and to become any blood cell. In fact, the results demonstrate that these cells have a high regenerative capacity once activated.

In the same study, the biological mechanisms that explain this phenomenon were further explored and it was found that IκBα reduces the levels of retinoic acid, which is basic in inducing cells into a state of quiescence, they remain inactive and do not differentiate. By eliminating IκBα, retinoic acid levels increase and this allows the cells to 'go to sleep' and thus "we are enriching a population of cells that is normally very scarce, but which performs the function of the most primitive stem cell, the one that is most conserved, and lasts throughout life," explains Dr. Bigas.

Despite their reduced number, the hematopoietic stem cells of the modified embryos still had the potential to become other cells. Moreover, when transplanted, they were activated and differentiated. As Dr. Bigas explains, "activating or inhibiting IκBα may allow us to have a tool to control the characteristics of blood stem cells and make it easier for these cells to fall asleep and remain in the state in which they were generated. In the future, we could induce the differentiation of embryonic cells into hematopoietic stem cells, prevent them from differentiating and have them available for transplantation into a patient."

For the time being, the only viable source of this type of treatment is a donation from a healthy person. Therefore, this study allows progress towards "the ultimate goal, which is to generate haematopoietic stem cells in the laboratory so that they can be used in multiple applications, from direct transplantation of stem cells to patients with leukaemia, to treatment with gene therapy for other disorders", says the head of the study. Although the work has been carried out with mouse embryos, the researchers are optimistic that the results can also be transferred to human cells.

Reference article

Thambyrajah, R., Maqueda, M., Fadlullah, M.Z. et al. IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development. Nat Commun 15, 4673 (2024). https://doi.org/10.1038/s41467-024-48854-5

More information

Servicio de Comunicación Hospital del Mar Research Institute/Hospital del Mar: Marta Calsina 93 3160680 mcalsina@researchmar.net, David Collantes 600402785 dcollantes@hospitaldelmar.cat

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