Hematopoietic stem cells (HSCs) populate our bone marrow and divide throughout our lifetimes to provide the red and white blood cells we need to live. However, during normal, healthy times, only particular HSCs are hard at work dividing and making new blood cells. The remaining HSCs are maintained in a protective dormant state. However, in response to blood loss or physiological stress of some sort, dormant HSCs must wake from their “slumbers” and begin dividing to make the needed blood cells. Such conditions, it turns out, can cause HSCs to experience a good deal of damage to their genomes. A paper that was published in Nature last year by Walter Dagmar and colleagues (Vol 520: pp. 549) showed that repeatedly subjecting mice to conditions that required the activation of dormant HSCs (in this case they injected the mice with polyinosinic:polycytidylic acid or pI:pC to mimic a viral infection and induce a type I interferon response) resulted in the eventual collapse of the bone marrow’s ability to produce new blood cells. The awakened HSCs accumulated such large quantities of DNA damage, that they were no longer able to divide and produce viable progeny. How then can HSCs maintain the integrity of their genomes while still dividing and making new blood cells?
The answer to this question is not completely clear, but a new paper in the December 2 edition of Science magazine provides new insights into HSC physiology and function. This paper by Yuki Taya and others, working in the laboratories of Hiromitsu Nakauchi at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine, and Satoshi Yamazaki from the University of Tokyo, has shown that amino acid metabolism plays a vital role in HSC maintenance. As it turns out, the amino acid concentrations in bone marrow are approximately 100-fold higher than the concentrations of these same amino acids in circulating blood. Taya and others reasoned that such high amino acid concentrations must exist for reasons other than protein synthesis. Therefore, they designed dietary regimens that depleted mice for specific amino acids. Sure enough, when mice were fed valine-depleted diets, the HSCs of those mice lost their ability to repopulate the bone marrow.
After only two weeks of valine depletion, several nooks and crannies of the bone marrow – so-called stem cell “niches” – were devoid of HSCs. The bone marrow of such mice was easily reconstituted with HSCs from donor mice without the need for radiation or chemical ablation treatments.
Taya and others found that vascular endothelial stromal cells in the bone marrow secrete valine and that this secreted valine (which, by the way, is a branched-chain amino acid) is integral for maintaining HSC niches.
The excitement surrounding this finding is plain, since using harsh chemicals or radiation to destroy the bone marrow (a procedure known as “myeloablation”) causes premature ageing, infertility, lousy overall health, and other rather unpleasant side effects. Therefore, finding a “kinder, gentler” way to reconstitute the bone marrow would certainly be welcomed by patients and their physicians. However, valine depletion, even though it does not affect sterility, did cause 50% of the mice to die once valine was restored to the diet. This is due to a phenomenon known as the “refeeding effect” which has also been observed in human patients. Such side effects could probably be prevented by gradually returning valine to the diet. Taya and others also showed that cultured human HSCs required valine and another branched-chain amino acid, leucine. Since both leucine and valine are metabolized to alpha-ketoglutatate, which is used as a substrate for DNA-modifying enzymes, these amino acids might exert their effects through epigenetic modifications to the genome.
More work is needed in this area, but the Taya paper is a welcomed finding to a vitally important field.