Every cloud has a silver lining

In this issue of Blood, Lewandowski and colleagues show that elevated extracellular ROS in the bone marrow are not just one of the signs of the damage induced by high doses of irradiation, but actually lead to up-regulation of VCAM-1 on endothelial cells, therefore mediating transplanted HSC homing and initial proliferation.¹ 

Reactive oxygen species (ROS) are used to our advantage by immune cells, which release them in bursts as a lethal weapon against a number of pathogens, but otherwise they tend to play the role of the bad guys in most stem cell studies. Side products of each cell's respiratory chain, they inevitably accumulate as a result of active metabolism. As they generate several types of damage at the protein, lipid, and DNA levels, ROS take much of the blame for cell and tissue aging. The detrimental effect of intracellular ROS for hematopoietic stem cell function is widely accepted, and it has been shown that antioxidant agents prolong hematopoietic stem cell (HSC) life.²  Although it is still debatable whether HSCs reside specifically in hypoxic niches in the bone marrow, it has been proposed that one of the advantages of a hypoxic niche would be to ensure that low ROS levels are maintained within the stem cell pool.³  While studying HSC homing patterns in lethally irradiated recipient mice, Lewandowski et al unveil a positive role for extracellular ROS during the early stages of bone marrow transplantation. They use a newly developed fiber optic–based probe to detect HSCs along the femur bone marrow of live mice from hours to days after transplantation, and analyze their image sequences to obtain a comprehensive picture of femur bone marrow repopulation kinetics, so far studied only using tissue sections^4,5  or through localized bone thinning.⁶  Live imaging of the whole bone cavity, similar to our previous analysis of bone marrow calvarium,⁷  leads to efficient analysis of the behavior of small numbers of purified HSCs. In the femur, HSCs seed and engraft preferentially in the epiphysis and, in particular, the femoral head, rich in trabecular marrow and vasculature. It would be interesting to know whether the vessels in this area are differentially affected by or react differently to irradiation compared with the ones in the bone shaft.

Lewandowski et al detect high levels of ROS in the irradiated bone marrow cavities and, surprisingly, impaired marrow seeding and HSC proliferation when ROS levels are diminished by antioxidant treatment. So how can ROS have a positive effect? The answer is in the vascular up-regulation of VCAM-1, an adhesion molecule already known to be involved not only in leukocyte trafficking to sites of infection but also in HSC homing and function.⁸  Antioxidant treatment reduces VCAM-1 expression and consequentially engraftment efficiency.

The presented data suggest that ROS, via modulation of VCAM-1 expression, contribute to the HSC sensing tissue damage and promptly starting the rescue process. Interestingly, the long-term outcome of HSC transplantation (ie, bone marrow complete engraftment and peripheral blood reconstitution) is the same whether the recipient mice are treated with antioxidants or not. The authors observe no difference in the outcome of secondary transplantations; however, previous work detected improved function of antioxidant-treated cells by the third serial transplantation. Bone marrow reconstitution after irradiation is highly demanding on HSCs, to the point that serially transplanted HSCs can be used to model stem cell aging. It is possible that ROS-mediated VCAM-1 induction evolved as a defense mechanism to ensure efficient response of all residual (or transplanted) HSCs, even though it triggers dangerously high levels of HSC metabolism. The consequential intracellular ROS accumulation would be but a little scar when the life of the irradiated subject is at stake.

Antioxidant treatment is widely regarded as a means to slow down HSC aging; however, we now know that it could hamper the initial steps of HSC engraftment after transplantation. The question now is whether it will be possible to identify a therapeutic window for antioxidant treatment in conjunction with bone marrow transplantation, allowing for HSC engraftment and rescue of the patient, but only minimally damaging the HSCs as a consequence of active cycling.