Low Intracellular Iron Levels May Keep Blood Stem Cells Young

Hematopoietic stem cells give rise to all blood cells in the body. Most of the time they are not dividing. Rather, they serve as a reserve for the times when the body needs rapid blood formation. “One of the reasons why we have this kind of cellular Swiss bank account [is to protect] the cellular integrity,” said Britta Will, a stem cell biologist at the Albert Einstein College of Medicine. Each cell division may harm the cells’ DNA and other macromolecules, so the very demanding task of daily blood cell production is instead accomplished by more committed descendants, namely progenitor blood cells that can differentiate into specific cell types. 

As individuals age, this cellular bank is not as readily available as in youth; the capacity of blood stem cells to self-renew declines. This reduced ability to replenish diverse blood cell types may result in impaired immune surveillance and contribute to the development of aging-associated cancers or other degenerative diseases. In a study published in Cell Stem Cell, Will and her colleagues showed that young mouse hematopoietic stem cells tightly regulate iron homeostasis to keep intracellular iron levels low, a capacity which may be lost during aging.¹ Furthermore, when researchers subjected them to additional iron restriction by using iron chelators, these cells activated a molecular response that is linked to their regenerative capacity. A treatment for intermittently removing excess iron in mice over the course of 13 months prevented the age-associated decline in these cells’ function. 

A serendipitous finding some years ago led Will and her colleagues to determine that a drug used to treat a condition associated with low blood platelet count also chelated, or removed, iron from hematopoietic stem cells. This stimulated regenerative function in mouse and human cells.² Interested in exploring this phenomenon further, the team monitored the available pool of iron and protein expression in blood stem cells of two- to three-month-old mice. 

The researchers found that the young cells activated key proteins to sense, transport, and store iron, tightly restricting its intracellular availability. When the researchers further restricted iron by using iron chelators, blood stem cells activated a limited iron response that encompassed iron import and mobilization to correct this deficit. The researchers found that this molecular response to iron restriction contributed to the cells’ regenerative function, while inhibiting it reduced this capacity. 

Single cell RNA sequencing analyses and other molecular techniques revealed the mechanism behind this link. Iron limitation increased the expression of Tat-interacting protein 60 kD (Tip60), an enzyme that epigenetically regulates gene expression. The researchers found that Tip60-dependent gene regulation during iron restriction led to increased fatty acid metabolism, which plays an important role in the self-renewal of these blood-forming cells.³ 

But as cells age, they may lose their ability to maintain iron homeostasis. To determine whether pharmacological iron limitation could help cells retain their regenerative capabilities during aging, Will and her colleagues injected six-month-old mice with an iron chelator for five consecutive days, repeating the treatment every four weeks for 13 months. At the end of the treatment, the hematopoietic stem cells from the treated aged mice showed a 10-fold increase in their blood formation capacity compared to those from untreated mice. “This was really, really striking,” said Will, who has received funds from Novartis Pharmaceuticals, which holds the patent on some iron chelators used in this study.    

While previous works suggested that iron may guide stem cell fate, the data in this new paper are interesting as they provide insight into the link between iron and age in blood stem cells, stated Pekka Katajisto, a stem cell biologist at the University of Helsinki and Karolinska Institute who did not participate in the study. 

However, researchers have a long way to go before considering manipulating iron levels in healthy individuals to renew or rejuvenate hematopoietic stem cells, Katajisto added. As of now, scientists do not know how the approach could harm other tissues. Yet, for specific diseases involving the hematopoietic system, “maybe this might be an interesting avenue to go,” Katajisto said.

References

1. Kao, Y-R, et al. An iron rheostat controls hematopoietic stem cell fate. Cell Stem Cell. 2024;31(3):378-397
2. Kao, Y-R, et al. Thrombopoietin receptor–independent stimulation of hematopoietic stem cells by eltrombopag. Sci Transl Med. 2018;10(458):eaas9563
3. Ito, K & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 2014;15(4):243-56