Many medical situations require a supply of red blood cells—anaemia, road accidents and chemotherapy, for example. But there is a genuine shortage of blood. Researchers throughout the world are therefore working hard to find solutions to alleviate these shortages, and their sights are set on the potential for creating an unlimited supply of red blood cells, platelets, etc., from stem cells as required. Naomi Taylor, an Inserm Research Director, and her team at the Molecular Genetics Institute of Montpellier (CNRS/Montpellier University) have just taken an important step in this direction. They show that two substances—glucose and glutamine—dictate the route taken by a blood stem cell in becoming a red blood cell or some other type of blood cell.
This research is published in the journal Cell Stem Cell.
The lifespan of a blood cell can vary greatly—from several decades for some lymphocytes to 120 days for a red blood cell, 8 days for platelets, or just 1 day for neutrophils. The body therefore has to replace some of these specific cell types on a daily basis to ensure that the requirement for “new” blood is met, while maintaining the equilibrium between the different types of blood cells.
Many research studies carried out in the last few decades have focused on elucidating the role of certain cytokines in promoting the multiplication of blood stem cells and their differentiation into red blood cells, white blood cells, or platelet precursor cells Thus EPO has become well known for stimulating and promoting the multiplication of red blood cells, whereas GM-CSF, for example, stimulates the multiplication of monocyte/macrophage type cells, the famous circulating “scavenger” cells Cytokines such as EPO and GM-CSF are used to help with haematopoietic reconstitution after surgery, during cancer chemotherapy, following a bone marrow transplant or during infection with the AIDS virus (HIV) for example.
However, it seems that these cytokines, although they play a decisive role, are not enough to ensure commitment to the various blood cell lineages. The question thus arises regarding the additional parameters and factors that direct the haematopoietic stem cells more effectively toward one cell type rather than another.
In the course of differentiation, many cell divisions take place during which the daughter cells acquire their unique characteristics. This process does not require energy alone; it also requires molecules such as amino acids, nucleotides and lipids to synthesise proteins, DNA and RNA, and membranes, respectively, for the new cells.
In the present study, Leal Oburoglu, a final year PhD student, showed that glutamine, the most abundant amino acid in the blood, is indispensable for a blood stem cell to become a red blood cell, particularly because it enables the production of nucleotides. Tests conducted in vitro in the laboratory and then in vivo in mice showed that blocking the use of glutamine or its transporter prevents blood stem cells from becoming red blood cells. Under these conditions, the blood stem cells will then differentiate into monocyte/macrophage type cells.
Conversely, if glucose breakdown to provide energy in the form of ATP (glycolysis) is prevented, nucleotide synthesis is then enabled. This has the overall effect of increasing the production of red blood cells from haematopoietic stem cells (erythropoiesis).
In other terms, the coordinated and targeted use of glutamine and glucose for nucleotide synthesis may enable the stem cell to provide more red blood cells.
For the first time, a study has brought to light that metabolic resources outside the cell control the destiny of the blood stem cell.
For Naomi Taylor and Sandrina Kinet, who coordinated this study: “It is fascinating to think that one day we may be able to bring about differentiation of blood stem cells ‘on demand’ by influencing the metabolic state of the cell.”
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