The In Vitro Response of Tissue Stem Cells to Irradiation With Different Linear Energy Transfers

Nagle, Peter W; Hosper, Nynke A.; Ploeg, Emily M.; Goethem, Marc-Jan van; Brandenburg, S.; Langendijk, Johannes A.; Chiu, Roland K.; Coppes, Robert P.

doi:10.1016/j.ijrobp.2016.02.020

Cited by 30 publications

(43 citation statements)

References 33 publications

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“…First, we show that the impact of a low dose of radiation on rat parotid gland saliva secretion may be greater than that of higher doses. We demonstrate that this response is mimicked by, but not limited to, murine salivary gland stem cells in 3D organoid cultures (9,(26)(27)(28) and is due to insufficient DDR activation at lower doses. Next, we show that human salivary gland stem cells also isolated from patient biopsies show this response.…”

Section: Introductionmentioning

confidence: 83%

“…Irradiation with X-rays was performed using the Xstrahl 200 Xray Therapy System at a voltage of 220 kV with a dose rate of 0.52 Gy/minute (26). SOBP C-ion irradiations were performed with (high LET) 90 MeV/u carbon ions in a 3.5-mm long SOBP with a diameter of 30 mm, allowing accurate irradiation of the cells.…”

Section: Irradiation Treatmentmentioning

confidence: 99%

“…These structures contain highly potent self-renewing stem cells that differentiate to all tissue lineages and are able to regenerate many tissues (9,24,25). Moreover, they enable the in vitro study of normal tissue stem cell responses to radiation (26). In this study, we use organoids to investigate the effects of low-dose irradiation on normal tissue stem cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

Nagle

Hosper

Barazzuol

et al. 2018

Clinical Cancer Research

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Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function. Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification. Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses <1 Gy, followed by relative radioresistance at doses ≥1 Gy, was observed in salivary gland and thyroid gland organoid cultures. DDR modulation resulted in diminished, or even abrogated, relative radioresistance. Furthermore, inhibition of the DDR protein ATM impaired DNA repair after 1 Gy, but not 0.25 Gy. Irradiation of patient-derived salivary gland organoid cells showed similar responses, whereas a single 1 Gy dose to salivary gland-derived stem cells resulted in greater survival than clinically relevant fractionated doses of 4 × 0.25 Gy. We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation.

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Section: Introductionmentioning

confidence: 83%

Section: Irradiation Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

Nagle

Hosper

Barazzuol

et al. 2018

Clinical Cancer Research

Self Cite

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“…described that subcutaneous adipose tissue, including the stem cells contained therein is sensitive to radiation. Since it is likely that if the bone marrow was ablated, necessitating a transplant, then the abdominal fat layer would also be heavily irradiated, the isolated cells would also likely be damaged or killed, and whether the cells would be fully functional is dependent on radiation dose (155). If the exposed individual has enough surviving cells, then they can be expanded and replace those lost to irradiation, functioning as well as cells from an unirradiated donor.…”

Section: Discussionmentioning

confidence: 99%

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop

et al. 2017

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In recent years, there has been increasing concern over the possibility of a radiological or nuclear incident occurring somewhere in the world. Intelligence agencies frequently report that terrorist groups and rogue nations are seeking to obtain radiological or nuclear weapons of mass destruction. In addition, there exists the real possibility that safety of nuclear power reactors could be compromised by natural (such as the tsunami and subsequent Fukushima accident in Japan in March, 2011) or accidental (Three Mile Island, 1979 and Chernobyl, 1986) events. Although progress has been made by governments around the world to prepare for these events, including the stockpiling of radiation countermeasures, there are still challenges concerning care of patients injured during a radiation incident. Because the deleterious and pathological effects of radiation are so broad, it is desirable to identify medical countermeasures that can have a beneficial impact on several tissues and organ systems. Cellular therapies have the potential to impact recovery and tissue/organ regeneration for both early and late complications of radiation exposure. These therapies, which could include stem or blood progenitor cells, mesenchymal stromal cells (MSCs) or cells derived from other tissues (e.g., endothelium or placenta), have shown great promise in treating other nonradiation injuries to and diseases of the bone marrow, skin, gastrointestinal tract, brain, lung and heart. To explore the potential use of these therapies in the treatment of victims after acute radiation exposure, the National Institute of Allergy and Infectious Diseases cosponsored an international workshop in July, 2015 in Paris, France with the Institut de Radioprotection et de Sûreté Nucléaire. The workshop included discussions of data available from testing in preclinical models of radiation injury to different organs, logistics associated with the practical use of cellular therapies for a mass casualty incident, as well as international regulatory requirements for authorizing such drug products to be legally and readily used in such incidents. This report reviews the data presented, as well as key discussion points from the meeting.

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“…However, in vitro plating efficacy does not always correlate with the fraction of CSCs in vivo, and the usability of in vitro clonogenic assay to evaluate CSC inactivation remains questionable [19e21]. Recent developments in threedimensional culture techniques allowing growth of patient CSC-containing tumour organoids [22] and subsequent organoid-based radiation survival studies [23] may become instrumental in the investigation of CSC dynamics.…”

Section: The Concept Of Cancer Stem Cells In Radiation Biologymentioning

confidence: 99%

Targeting Stem Cells in Radiation Oncology

Coppes

Dubrovska

2017

Clinical Oncology

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The In Vitro Response of Tissue Stem Cells to Irradiation With Different Linear Energy Transfers

Abstract: Mouse SGSC radiosensitivity seems reduced at higher LET radiation compared with transformed HSG cells. The developed model to assess the radiation response of SGSCs offers novel possibilities to study the radiation response of normal tissue in vitro.

Cited by 30 publications

References 33 publications

Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

Lack of DNA Damage Response at Low Radiation Doses in Adult Stem Cells Contributes to Organ Dysfunction

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop

Targeting Stem Cells in Radiation Oncology

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