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 (Lgr5+mice) and its GI tumor surrogate (Lgr5+Apc1638N/+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 following28Si 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) after28Si exposure. Moreover, gene expression of pro-inflammatory and pro-growth SASP factors remained persistently elevated for up to a year post-28Si irradiation. Additionally, p38 MAPK and NF-κB signaling pathways, which are critical for stress responses and inflammation, were also upregulated after28Si radiation. Transcripts involved in nutrient absorption and barrier function were also altered following irradiation. InLgr5+Apc1638N/+mice, tumor incidence was significantly higher in those exposed to28Si radiation compared to the spontaneous tumorigenesis observed in control mice. Our results indicate that high-LET28Si 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，具有高电离密度特性，对维持肠道稳态至关重要的肠道干细胞构成风险。先前研究表明，重离子辐射可导致小鼠肠黏膜出现慢性氧化应激、持续性DNA损伤、细胞衰老及衰老相关分泌表型。然而，其对不同细胞类型的具体影响，特别是对维持细胞稳态、胃肠道功能及基因组应激下肿瘤发生至关重要的Lgr5+肠道干细胞，目前研究尚不充分。本研究利用肠道干细胞相关小鼠模型（Lgr5+小鼠）及其胃肠道肿瘤替代模型（Lgr5+Apc1638N/+小鼠），探究了高线性能量转移辐射后肠道干细胞的特异性分子改变。在照射后2、5和12个月对组织切片进行衰老及衰老相关分泌表型信号评估。与γ射线或对照组相比，28Si辐射后Lgr5+细胞表现出显著更强的氧化应激。Lgr5+细胞和潘氏细胞在28Si照射后均呈现衰老特征并形成衰老相关分泌表型。此外，促炎和促生长衰老相关分泌表型因子的基因表达在28Si照射后持续升高长达一年。同时，对应激反应和炎症至关重要的p38 MAPK与NF-κB信号通路在28Si辐射后也出现上调。辐射后参与营养吸收和屏障功能的转录本也发生改变。在Lgr5+Apc1638N/+小鼠中，接受28Si辐射组的肿瘤发生率显著高于对照组自发性肿瘤形成。我们的研究结果表明，高线性能量转移28Si辐射可诱导Lgr5+肠道干细胞产生持续性DNA损伤、氧化应激、衰老及衰老相关分泌表型，这可能使宇航员在长期太空任务期间及后续阶段面临营养吸收改变、屏障功能异常及胃肠道癌变的风险。
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