Haematologica | 2021
Low-dose ionizing radiations leave scars on human hematopoietic stem and progenitor cells: the role of reactive oxygen species
Abstract
After Röntgen’s discovery in 1895, an X-ray became a game changer in medicine. It was discovered as an invisible ray of light that passes through many objects, including human bodies, and visualizes the internal organs and structures as silhouettes. As now seen in medical radiography, such as chest X-rays and computed tomography (CT) scans, ionizing radiation (IR) has enabled investigation of deep tissues in humans that had been otherwise impossible without surgical intervention, contributing to the early detection and treatment of many diseases. However, as is often the case with new medicine, were shown to have a biohazard effect. They are identified as a type of IR: a stream of high energy photons that are strong enough to ionize atoms and disrupt molecular bonds in biomolecules, including DNA. As DNA encodes an essential blueprint of a cell, the DNA-damaging property of IR can be toxic. This effect, although used for killing cancer cells in radiotherapy, has raised concerns about the effect of IR on normal tissues and whether the benefits exceed the risks. Modern medicine relies heavily on radiography to assess human health. The annual doses of IR people receive are increasing. A recent study estimated that around 2% or 4,000,000 of the non-elderly adults in the US receive 20 milligray (mGy) or more per year due to medical requirements. Historically, risks associated with low-dose IR are considered to be almost negligible as it does not cause any acute toxicity, nor does it increase the risk of carcinogenesis, based on empirical linear fits of existing human data determined at high doses, such as those of Japanese atomic bomb survivors. Indeed, low-dose IR rarely induces DNA double strand breaks (DSB), which often cause mutations and are considered to be the most relevant lesion for the deleterious effects of IR. However, even though low-dose IR rarely cause DSB, they are reportedly less easy to repair than those induced by high-dose IR . Importantly, recent evidence suggests that cumulative doses of 50 mGy IR (doses equivalent to 5-10 brain CT scans when given in childhood) have longterm detrimental effects on human health, including a more than 3-fold increase in the risks of acute lymphoblastic leukemia and myelodysplastic syndrome. Furthermore, mouse studies demonstrate that low-dose IR affect function of long-lived tissue-specific stem cells, including hematopoietic stem cells (HSC). Thus, understanding the persistent effect of low-dose IR on human tissue-specific stem cells is of particular importance in precisely evaluating the risks posed by radiography on public health. In this issue of Haematologica, Henry et al. compared the effects of low and high doses of IR on hematopoietic stem and progenitor cells (HSPC) obtained from human umbilical cord blood (CB) (Figure 1). HSPC sustain themselves via self-renewing ability, and give rise to all of the blood lineage cells, such as innate and acquired immune cells, erythrocytes and platelets, through multi-lineage differentiation. They found that a single dose of 20 mGy IR is sufficient to impair the self-renewing capacity of CB HSPC. Intriguingly, this effect is independent of canonical DNA damage response (DDR), as a 20 mGy dose fails to induce DSB markers γH2AX and 53BP1 foci, or DDR hallmarks phospho-ATM and -p53, all of which are induced by a 2.5 Gy dose. Instead, the authors demonstrate that it is mediated by reactive oxygen species (ROS), a highly reactive oxygen byproduct mainly generated via the cell respiratory process of oxidative phosphorylation (OXPHOS) in mitochondria, and p38/MAPK14, a key enzyme that, upon elevation of ROS, sends a signal to HSPC to inhibit their self-renewing potential. Thus, the results of Henry et al. indicate that low-dose IR impair human CB HSPC function through ROS and p38/MAPK14, but not via canonical DDR via ATM or p53. The high sensitivity of HSC to elevated levels of ROS is well established, first in ATM deficiency and later in the contexts of other stress conditions. Similarly, p38/MAPK14 activation in response to ROS elevation is identified as a common downstream pathway responsible for impairment of self-renewal in HSC. In contrast, what In the article by Yamashita M and Suda T entitled “Low-dose X-rays leave scars on human hematopoietic stem and progenitor cells: the role of reactive oxygen species” published in Haematologica 2020;105(8):1986-1988: