Periodic Reporting for period 3 - VitASTEM (Regulation of Single Hematopoietic Stem Cells by Intake of Vitamin A)
Reporting period: 2021-05-01 to 2022-10-31
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. 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. VitASTEM aims to address: how does vitamin A regulate the deep sleep of HSCs? and can we modulate the resting state of blood stem cells by changing our dietary habits? The overall goal is to discover how a component of our diet influence blood stem cells and make this knowledge useful in the context of combating human diseases.
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. During this period of funding, we have already established sensitive measurement 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. Importantly, we found that blood stem cells are regulated by an unconventional vitamin A pathway. In addition, we have performed extensive functional analysis to show that this unconventional vitamin A pathway plays an important role in the maintenance of stemness.
We expect to address whether we can modulate the levels of dietary vitamin A to maintain a healthy hematopoietic stem cell pool and understand the underlying molecular regulatory mechanisms. To this end, we will setup distinct diets containing different levels of vitamin A and analyze the blood stem cell compartment upon aging. To address the mechanism we will perform extensive functional analysis (e.g. loss- and gain-of-function experiments). Further, we plan to address whether the loss of blood stem cells in the context of vitamin A deficiency is an (ir)reversible process. To this end, we will add vitamin A in the diet after several weeks of deficiency and analyze the stem cell compartment.
Overall, the here established techniques will also allow us to investigate the effects of other dietary habits on blood stem cells. In addition, it has been shown that deregulated metabolism of stem cells supports the progress of blood cancer. Thus, in future studies the here discovered unconventional vitamin A pathway might be considered to be targeted as treatment in pathologies such as blood cancer.
Overall, the here established techniques will also allow us to investigate the effects of other dietary habits on blood stem cells. In addition, it has been shown that deregulated metabolism of stem cells supports the progress of blood cancer. Thus, in future studies the here discovered unconventional vitamin A pathway might be considered to be targeted as treatment in pathologies such as blood cancer.