A team of researchers has uncovered a new way in which blood stem cells react to severe anemia by altering lipoprotein metabolism. While it has been established how immediate erythroid precursors respond during acute anemia, the behavior of more immature stem cells was previously unknown. The insights gained from this study could help create new treatments for patients suffering from severe anemia who do not benefit from current therapies.
Red blood cells are the most plentiful type of cells in the body. It has been recognized for a long time that when red blood cells degrade or anemia arises from bleeding, the hormone erythropoietin (EPO) increases, stimulating the growth of immature cells called erythroblasts, which eventually mature into red blood cells and restore their numbers. However, the response of more primitive “hematopoietic stem cells” to severe anemia has remained mostly unclear. Although hematopoietic stem cells can generate all blood cell types, they lack erythropoietin receptors, indicating that another unknown mechanism may support the recovery of red blood cells.
To understand this better, the research team caused acute anemia in mice by using a drug (phenylhydrazine) that destroys red blood cells or through blood loss (phlebotomy) and then studied the changes in hematopoietic stem cells within the bone marrow to determine how these changes occurred.
The study found that hematopoietic stem cells began to multiply right after acute anemia was induced. Furthermore, the stem cells in anemic mice generated more red blood cells than other types of blood cells, a reaction not observed in normal mice. Since these stem cells do not respond to erythropoietin, the researchers performed genetic analyses to pinpoint what triggers their changes. They discovered that genes associated with lipid metabolism were activated shortly after the onset of anemia, notably increasing the activity of the very low-density lipoprotein receptor (VLDLR).
Additionally, the research differentiated two types of hematopoietic stem cells based on their VLDLR expression: those with high levels (VLDLRhigh) and those with low levels (VLDLRlow). The VLDLRhigh stem cells were more inclined to produce red blood cells. Analysis of lipids and related proteins in the bone marrow of anemic mice revealed that while levels of VLDL dropped, apolipoprotein E (ApoE)—a key component of VLDL—quickly increased. In genetically altered mice lacking ApoE, hematopoietic stem cells did not ramp up red blood cell production when faced with anemia.
Further genetic analysis indicated that ApoE impacting VLDLRhigh stem cells weakened the activity of the Erg gene, which helps sustain the stem cells’ properties and inhibits their transition to other cell types. Notably, giving synthetic ApoE or reducing Erg activity made healthy mice’s hematopoietic stem cells more likely to produce red blood cells. These findings imply that in response to acute anemia, ApoE is released from VLDL and uniquely targets VLDLRhigh hematopoietic stem cells, enhancing their capability to produce red blood cells.
Considering the significance of these results, they could be the foundation for new strategies to combat anemia. Although erythropoietin is currently utilized as a treatment for anemia, some patients show minimal reactions to it. Moreover, existing anemia treatments, such as iron supplements and blood transfusions, can result in iron build-up in the body, leading to additional health complications. The insights from this study unveil a new mechanism of red blood cell generation that deviates from traditional pathways, potentially facilitating the creation of innovative treatments for patients with severe anemia who have not responded adequately to established therapies.
