Regulation of Single Hematopoietic Stem Cells by Intake of Vitamin A

Informazioni relative al progetto

VitASTEM

ID dell’accordo di sovvenzione: 759206

DOI

10.3030/759206

Progetto chiuso

Data della firma CE 4 Ottobre 2017

Data di avvio 1 Maggio 2018

Data di completamento 30 Aprile 2024

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 500 000,00

Contributo UE

€ 1 500 000,00

Coordinato da

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)

Periodo di rendicontazione: 2022-11-01 al 2024-04-30

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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,.).

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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