Abstract
DNA-double strand break (DSB), detected by immunostaining of key proteins orchestrating repair, like γH2AX and 53BP1, is well established as a surrogate for tissue radiosensitivity. We hypothesized that the generation of normal brain 3D organoids (“mini-brains”) from human induced pluripotent stem cells (hiPSC) combined with detection of DNA damage repair (DDR) may hold the promise towards developing personalized models for the determination of normal tissue radiosensitivity. In this study, cerebral organoids, an in vitro model that stands in its complexity between 2D cellular system and an organ, have been used. To quantify radiation-induced response, immunofluorescent staining with γH2AX and 53BP1 were applied at early (30 min, initial damage), and late time points (18 and 72 h, residual damage), following clinical standard 2 Gy irradiation. Based on our findings, assessment of DDR kinetics as a surrogate for radiosensitivity in hiPSC derived cerebral organoids is feasible. Further development of mini-brains recapitulating mature adult neuronal tissue and implementation of additional signaling and toxicity surrogates may pave the way towards development of next-generation personalized assessment of radiosensitivity in healthy neuronal tissue.
Highlights
Organoids derived from human induced pluripotent stem cells (hiPSC) have emerged as a great tool in translational research, as they are allowing researches to get closer to personalized medicine treatment [1].brain organoids are able to recapitulate cellular complexity and structural organization of this organ, even different brain regions depending on their in vitro conditions: optic cup [2,3], spinal [4,5], midbrain [6,7], hippocampal [8], and cerebral [9,10,11]organoids, the last being used in this study
Organoids derived from hiPSCs have emerged as a great tool in translational research, as they are allowing researches to get closer to personalized medicine treatment [1]
2D cell-line co-culture systems or patient-derived xenografts, in understanding complex cellular interactions within and between tumor and surrounding healthy tissue cells. This unique cellular interplay might be reflecting patients’ specific characteristics, such as inherent radiosensitivity, which may be important for predicting side-effects of radiotherapy [16,17,18]. When it comes to radiation treatment for different brain tumors, a common problem is partial success due to transient response and tumor reoccurrence [19], and healthy tissue response
Summary
Organoids derived from hiPSCs have emerged as a great tool in translational research, as they are allowing researches to get closer to personalized medicine treatment [1]. Development of patient-derived organoids represents a significant step forward, compared to When it comes to radiation treatment for different brain tumors, a common problem is partial success due to transient response and tumor reoccurrence [19], and healthy tissue response. It is common, in cancer patients with long-term survival, to develop radiation-induced brain necrosis, which in time may lead to cognitive disabilities [20]. Cells) following radiation treatment [21,29]
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