Effects of low radiation doses on stem cells
Epidemiological studies have provided a wealth of information on the impact of ionising radiation on cancer risk. Survivors of the Hiroshima/Nagasaki atomic bombings or individuals that have been exposed to radiation for occupational, medical and environmental reasons have provided the data. However, the impact of low radiation doses on health are uncertain, largely relying on extrapolation estimates from higher radiation doses and are not based on a complete understanding of the biological responses of stem cells, from which cancers originate. Research is required to ensure the risk extrapolation model employed accurately reflects all underlying biological mechanisms. Stem cells exist in the body for long periods of time, regulate homeostatic tissue regeneration and may be subjected to genotoxic damage. As a result of extrinsic factors such as ionising radiation or intrinsic DNA damage, the stem cells could acquire irreversible errors. Such damage normally triggers apoptosis, senescence or a transformation that can ultimately lead to cancer. The EU-funded RISK-IR project addressed this issue by applying past and present knowledge of stem cell biology, and using state-of-the-art technologies to investigate the effect of ionising radiation at low doses (<100 mGy) and dose-rates (<6 mGymin-1) on different types of stem cells. The consortium employed various experimental model systems including human cells and mice to perform the work. ‘The studies undertaken aimed to help understand the mechanisms of radiation-mediated carcinogenesis and these are applicable in all species, including humans,’ explains project coordinator Simon Bouffler. Stem cell models unveil low radiation effects Researchers observed hypersensitivity to low dose radiation in certain stem cells associated with oxidative stress response and energy metabolism. In human and mouse haematopoietic stem cells, exposure to low doses of ionising radiation affected cell function and also had a long-term impact due to deficits in repopulating stem cells. In contrast, skin stem cells were resistant to low radiation doses even in follow-up studies a couple of years after exposure. The RISK-IR team studied human bone marrow mesenchymal stem cells (MSCs) that, given their capacity to differentiate into bone, cartilage, and fat, support haematopoiesis and contribute to the body's homeostasis. They discovered an age-related response to radiation and DNA repair capacity directly linked to MSC cycling state. Extending these investigations into mouse models predisposed to cancer, an association was observed between low dose radiation and basal cell carcinoma. Contrary observations were made for squamous cell carcinoma, suggesting a tissue-specific effect of radiation exposure. Using inducible pluripotent stem cell models, researchers observed that high dose irradiation prevented reprogramming in vitro, while exposure to lower doses may have an inhibitory effect. Furthermore, secreted factors including IL-6 appear to facilitate reprogramming. Investigation of the DNA damage response caused by low dose radiation in embryonic stem cells unveiled a time- and dose-dependent effect strongly linked to reactive oxygen radicals. Safety impact Ionising radiation has many uses in industrial and medical contexts, and exposure can sometimes be unavoidable. ‘We need to ensure our key findings are communicated and recognised by the major international review/standards bodies such as the United Nations Scientific Committee on the Effects of Atomic Radiation and the International Commission of Radiological Protection’ states Dr Bouffler. Quantifying the risk at low radiation doses is fundamental for radiation protection. Therefore, the RISK-IR project results will contribute to the development of biologically-realistic risk projection models. Importantly, they will add to the scientific evidence and help formulate future guidelines on radiation exposure, balancing the risks and benefits of ionising radiation.
Keywords
Radiation, stem cells, RISK-IR, MSC, DNA damage response
