Page 10 - 2020_08-Haematologica-web

EDITORIALS
Low-dose X-rays leave scars on human hematopoietic stem and progenitor cells: the role of reactive oxygen species
Masayuki Yamashita1 and Toshio Suda2,3
1Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 2International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan and 3Cancer Science Institute, National University of Singapore, Singapore
E-mail: TOSHIO SUDA - sudato@keio.jp doi:10.3324/haematol.2020.254292
After Röntgen’s discovery in 1895, an X-ray became a game changer in medicine.1 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 radiog- raphy, such as chest X-rays and computed tomography (CT) scans, X-rays have enabled investigation of deep tissues in humans that had been otherwise impossible without surgical intervention, contributing to the early detection and treat- ment of many diseases. However, as is often the case with new medicine, X-rays were shown to have a biohazard effect.2 They are identified as a type of ionizing radiation (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 X-rays can be toxic. This effect, although used for killing cancer cells in radiotherapy, has raised concerns about the effect of X-rays on normal tis- sues and whether the benefits exceed the risks.
Modern medicine relies heavily on radiography to assess human health. The annual doses of X-rays 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 milli- gray (mGy) or more per year due to medical requirements.3 Historically, risks associated with low-dose IR are consid- ered 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 sur- vivors.4 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.5 However, even though low-dose X-rays rarely cause DSB, they are reportedly less easy to repair than those induced by high-dose X-rays.6 Importantly, recent evidence suggests that cumulative doses of 50 mGy X-ray (doses equivalent to 5-10 brain CT scans when given in childhood) have long-term detrimental effects on human health, includ- ing a more than 3-fold increase in the risks of acute lym- phoblastic leukemia and myelodysplastic syndrome.7 Furthermore, mouse studies demonstrate that low-dose X- rays affect function of long-lived tissue-specific stem cells, including hematopoietic stem cells (HSC).8,9 Thus, under- standing the persistent effect of low-dose X-rays on human tissue-specific stem cells is of particular importance in pre- cisely 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 X-rays on hematopoietic stem and progenitor cells (HSPC) obtained from human umbilical cord blood (CB) (Figure 1).10 HSPC sustain them-
selves 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 differ- entiation. They found that a single dose of 20 mGy X-rays 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 γ−H2AX 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 mediat- ed by reactive oxygen species (ROS), a highly reactive oxy- gen byproduct mainly generated via the cell respiratory process of oxidative phosphorylation (OXPHOS) in mito- chondria, and p38/MAPK14, a key enzyme that, upon eleva- tion of ROS, sends a signal to HSPC to inhibit their self- renewing potential.11 Thus, the results of Henry et al. indicate that low-dose X-rays 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 con- texts of other stress conditions.11-13 Similarly, p38/MAPK14 activation in response to ROS elevation is identified as a common downstream pathway responsible for impairment of self-renewal in HSC.11,12 In contrast, what is often unclear is the upstream mediator that causes ROS elevation. In the context of low-dose IR, mouse studies have uncovered the hypersensitivity of HSC and esophageal stem cells to low- dose IR that is mediated by ROS elevation, although the molecular link between low-dose IR and elevated ROS has not yet been investigated.8,9 It is estimated that approximate- ly 90% of ROS can be generated during OXPHOS in mito- chondria,14 mainly through functions of complexes I and III.15 Interestingly, the results shown by Henry et al. indicate that ROS elevation in human CB HSPC upon exposure to 20 mGy X-rays is closely associated with loss of mitochondrial membrane potential, which reflects a decrease in proton gra- dient across the cristae and often correlates with mitochon- drial dysfunction.10 Apart from nucleus, mitochondria are the only organelle in mammalian cells that contain DNA, which can also be damaged by low-dose IR.16 Mitochondrial DNA (mtDNA) encodes proteins that consist of complexes I and ATP synthase, both of which are essential for proper elec- tron transport and OXPHOS. Of note, these components are located in the so-called “common deletion” region of mtDNA that is commonly deleted upon exposure to low- dose IR. mtDNA is not protected by histones, and is thus potentially more susceptible to IR-induced damage com- pared to nuclear DNA. Moreover, mtDNA is located in matrix inside inner membranes where ROS is generated, and is thus more greatly affected by IR-induced oxidative stress
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haematologica | 2020; 105(8)