Kumar Santosh, Suman Shubhankar, Angdisen Jerry, Moon Bo-Hyun, Kallakury Bhaskar V S, Datta Kamal, Fornace Albert J
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA.
Cancers (Basel). 2024 Oct 4;16(19):3392. doi: 10.3390/cancers16193392.
Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses a risk to intestinal stem cells (ISCs), which are vital for maintaining intestinal homeostasis. Earlier studies have shown that heavy-ion radiation can cause chronic oxidative stress, persistent DNA damage, cellular senescence, and the development of a senescence-associated secretory phenotype (SASP) in mouse intestinal mucosa. However, the specific impact on different cell types, particularly Lgr5 intestinal stem cells (ISCs), which are crucial for maintaining cellular homeostasis, GI function, and tumor initiation under genomic stress, remains understudied. Using an ISCs-relevant mouse model ( mice) and its GI tumor surrogate ( mice), we investigated ISCs-specific molecular alterations after high-LET radiation exposure. Tissue sections were assessed for senescence and SASP signaling at 2, 5 and 12 months post-exposure. Lgr5+ cells exhibited significantly greater oxidative stress following Si irradiation compared to γ-ray or controls. Both Lgr5 cells and Paneth cells showed signs of senescence and developed a senescence-associated secretory phenotype (SASP) after Si exposure. Moreover, gene expression of pro-inflammatory and pro-growth SASP factors remained persistently elevated for up to a year post-Si irradiation. Additionally, p38 MAPK and NF-κB signaling pathways, which are critical for stress responses and inflammation, were also upregulated after Si radiation. Transcripts involved in nutrient absorption and barrier function were also altered following irradiation. In mice, tumor incidence was significantly higher in those exposed to Si radiation compared to the spontaneous tumorigenesis observed in control mice. Our results indicate that high-LET Si exposure induces persistent DNA damage, oxidative stress, senescence, and SASP in Lgr5 ISCs, potentially predisposing astronauts to altered nutrient absorption, barrier function, and GI carcinogenesis during and after a long-duration outer space mission.
重离子辐射在外层空间普遍存在且与放射治疗相关，它具有密集的电离作用，对肠道干细胞（ISC）构成风险，而肠道干细胞对于维持肠道内环境稳定至关重要。早期研究表明，重离子辐射可导致慢性氧化应激、持续性DNA损伤、细胞衰老以及小鼠肠黏膜中衰老相关分泌表型（SASP）的形成。然而，对于不同细胞类型的具体影响，尤其是对Lgr5肠道干细胞（ISC）的影响，仍研究不足。Lgr5肠道干细胞对于在基因组应激下维持细胞内环境稳定、胃肠道功能以及肿瘤起始至关重要。我们使用与ISC相关的小鼠模型（小鼠）及其胃肠道肿瘤替代模型（小鼠），研究了高传能线密度（LET）辐射暴露后ISC特异性的分子改变。在暴露后2个月、5个月和12个月评估组织切片的衰老和SASP信号。与γ射线或对照组相比，硅（Si）辐射后Lgr5 +细胞表现出明显更大的氧化应激。Si暴露后，Lgr5细胞和潘氏细胞均显示出衰老迹象并形成了衰老相关分泌表型（SASP）。此外，促炎和促生长SASP因子的基因表达在Si辐射后长达一年的时间里持续升高。此外，对应激反应和炎症至关重要的p38丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路在Si辐射后也上调。辐射后参与营养吸收和屏障功能的转录本也发生了改变。在小鼠中，与对照小鼠中观察到的自发肿瘤发生相比，暴露于Si辐射的小鼠肿瘤发生率显著更高。我们的结果表明，高LET Si暴露在Lgr5 ISC中诱导持续性DNA损伤、氧化应激、衰老和SASP，这可能使宇航员在长期外层空间任务期间及之后更容易出现营养吸收改变、屏障功能改变和胃肠道癌变。
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