Regulation of Single Hematopoietic Stem Cells by Intake of Vitamin A

Información del proyecto

VitASTEM

Identificador del acuerdo de subvención: 759206

DOI

10.3030/759206

Proyecto cerrado

Fecha de la firma de la CE 4 Octubre 2017

Fecha de inicio 1 Mayo 2018

Fecha de finalización 30 Abril 2024

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 500 000,00

Aportación de la UE

€ 1 500 000,00

Coordinado por

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 4 - VitASTEM (Regulation of Single Hematopoietic Stem Cells by Intake of Vitamin A)

Período documentado: 2022-11-01 hasta 2024-04-30

Resumen del contexto y de los objetivos generales del proyecto

Since billions of blood cells die every day, the same amount of cells need to be produced daily to maintain the steady-state. This process is mediated by our hematopoietic stem cells (HSCs). Most potent HSCs are surprisingly in a state of deep dormancy to built an emergency reservoir. This is a safety measure of stem cells to prevent the acquisition of mutations, which could lead to blood cancer (leukemia). As a reaction to stress, such as blood loss or infections, dormant HSCs are activated in order to quickly regenerate the blood system. HSCs rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. We recently found that Vitamin A / retinoic acid - a component of our food- is controlling blood stem cell function. Vitamin A deficiency currently affects mostly young children in developing countries and leads to blindness and a weakened immune system. The consequence is that infectious diseases that show an inconspicuous course in healthy conditions can become a death risk for affected children. This weakening of the immune system is often irreversible since only 20% of children recover even upon vitamin A administration. The reason for this observation is unknown. Our research suggests that this could possibly be caused by the blood stem cell loss. Specifically, we found that vitamin A keep HSCs in the sleep-like, dormant state protecting them from exhaustion and maintaining their long-term differentiation potential. In VitASTEM we uncovered a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Further, in VitASTEM we established state-of-the-art low input technologies and generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We can only find a few thousands of blood stem cells in an organism. One of the main challenges working with blood stem cells is exactly the small number of cells with which we have to carry out our experiments. In VitASTEM we have established sensitive omics methods, which have allowed us to carry out an extensive analysis of blood stem cells and further differentiated precursor populations. The application of these methods has allowed us to decipher how HSCs are regulated. Specifically, by combining genome-wide transcriptome, epigenome and metabolomics methods, we have identified the dietary/metabolic needs of blood stem cells. We uncovered a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Further, in VitASTEM we established state-of-the-art low input technologies and generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
We have presented our data in numerous conferences (e.g. ISEH, GSCN, EHA,.), and diverse public outreaching events (Max Planck day, Pint of science,.).

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

In VitASTEM we uncovered a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Further, in VitASTEM we established state-of-the-art low input technologies and generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.

Graphical abstratc main results VitASTEM