Mouse intestinal Lgr5+ stem cells are more sensitive to heavy ion irradiation than Bmi1+ stem cells
Mouse intestinal Lgr5+ stem cells are more sensitive to heavy ion irradiation than Bmi1+ stem cells
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小鼠肠道Lgr5干细胞比Bmi1干细胞对重离子照射更敏感
DOI：
10.1093/abbs/gmy158
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发表时间：
2018
影响因子：
3.7
通讯作者：
Guangming Zhou
中科院分区：
文献类型：
--
作者：
Anqing Wu ;Wentao Hu ;Jian Zhang ;Guo Ziyang ;Cuihua Liu ;Takanori Katsube ;Kaoru Tanaka ;Jing Nie ;Bing Wang ;Guangming Zhou
在人类探索火星或其他长期的外层空间任务之前，必须准确地估计和减轻由空间辐射引起的癌症和其他辐射损伤的风险，所述空间辐射包含高线性能量转移（LET）粒子，例如重离子。另一方面，加速碳离子已成功用于临床肿瘤治疗，其对正常组织的损伤也备受关注。因此，重离子粒子不仅对载人航天探测，而且对正在接受粒子放射治疗的患者都有严重的风险[1，2]。早期研究认为，肠道是一种辐射敏感组织，在γ射线、X射线等低LET辐射后，肠道受到严重损伤，丧失了个体生存的主要消化吸收功能。但是，由于缺乏足够的体内机制数据，重离子引起的肠道损伤的认识还存在很大的不确定性。在这里，我们第一次证明了Bmi 1表达细胞比Lgr 5+细胞在小鼠肠道中对碳离子更具抵抗力，并且可能是碳离子辐射诱导的肠损伤后肠细胞自我更新的主要干细胞。图1A示出了小鼠的存活曲线，其全身暴露于四种剂量（5.5、6、6.5和7戈伊）的碳离子。结果发现，7和6.5戈伊的碳离子辐照对小鼠造成严重损伤，这两组小鼠在18天内全部死亡。在6和5.5戈伊剂量组中，辐射诱导的致死率要低得多，在30天存活试验中分别有30%和90%的小鼠存活。死亡后，分析6.5和7戈伊组小鼠的肠道，观察到严重的损害。高剂量碳离子暴露刺激肠粘膜通透性增加，肠道中充满大量粘液粪便，炎症加剧（图1 B）。这些结果表明，在较高剂量（6.5和7戈伊）的碳离子暴露后，所有小鼠在18天内死亡，推测这是由辐射诱导的造血系统损伤和肠道消化功能障碍引起的。肠道中存在着多种不同功能、不同部位的细胞，如绒毛上皮细胞、隐窝干细胞等。遭受严重辐射后，敏感的上皮细胞会在高氧化应激下死亡[3]。如果照射后隐窝中的干细胞存活下来，并能及时分化为上皮细胞进行更新，则可减轻放射损伤引起的死亡。因此，保护干细胞并诱导其活性是治疗肠放射损伤的有效途径。早期的研究表明，肠干细胞（ISCs）具有两种细胞表型，即Lgr 5或Bmi 1阳性细胞，两者都位于隐窝中[4]。在低LET辐射时，高于10 Gy的剂量主要引起胃肠道损伤，并导致腹泻、脱水、败血症和肠出血，最终在辐射后10-15天内死亡[5]。最近，研究表明Lgr 5+干细胞对X射线辐射比肠道中的其他干细胞更敏感，并且在辐射后24小时显著减少[6]。在目前的研究中，我们观察到一个类似的现象，使用重离子辐照
Before the human exploration of the Mars or other long-duration missions in outer space, the risks of cancer and other radiation injury induced by space radiations, containing high linear energy transfer (LET) particles such as heavy ions, must be accurately estimated and mitigated. On the other hand, accelerated carbon ions have been successfully used for clinical tumor treatment, and their damages to normal tissues are also of concern. Therefore, heavy ion particles are severely risky not only to manned space exploration but also to the patients experiencing particle radiotherapy [1, 2]. Earlier studies suggested that intestine was a radio-sensitive tissue which was seriously injured, and then lost main digestionabsorption function for individual survival after low LET radiation such as γ-rays and X-rays. But there is much uncertainty in understanding heavy-ion-induced intestinal injury because sufficient in vivo mechanistic data are not available. Here, we demonstrate for the first time that the Bmi1-expressing cells are more resistant to carbon ions than Lgr5+ cells in mouse intestine and may be the major stem cells for the self-renewal of intestinal cells after intestinal injury induced by carbon ion irradiation. Figure 1 A shows the survival curves of mice of which the whole body was exposed to carbon ions at four doses (5.5, 6, 6.5, and 7 Gy). It was found that 7 and 6.5 Gy of carbon ion irradiations caused severe injury to the mice, and all mice in these two groups died within 18 days. In the 6 and 5.5 Gy groups, radiation-induced lethality was much lower, 30% and 90% of the mice survived in the 30-day survival test, respectively. After death, the intestinal tracts of mice in the 6.5 and 7 Gy groups were analyzed and serious damage was observed. High-dose carbon ion exposure stimulated enhanced permeability of the intestinal mucosa and exacerbation of inflammation with so much mucous stool filled in the intestine (Fig. 1 B). These results suggest that after higher doses (6.5 and 7 Gy) carbon ion exposures, all mice died in 18 days, which is speculated to be caused by radiation-induced hematopoietic system damage and intestinal digestive dysfunction. There are so many kinds of cells with different functions and different locations in intestine, such as villus epithelial cells and crypt stem cells. Suffering a severe radiation, sensitive epithelial cells will die in high oxidative stress [3]. If the stem cells in crypt survived the irradiation and could timely differentiate into epithelial cells for renewal, radiation injury-induced death would be mitigated. So, protecting stem cells and inducing their activity are effective ways to treat intestinal radiation injury. Earlier studies suggested that intestinal stem cells (ISCs) have two cellular phenotypes as Lgr5 or Bmi1 positive cells, both of which are located in the crypt [4]. Upon low LET radiation, doses higher than 10Gy mainly cause gastrointestinal damage and result in diarrhea, dehydration, sepsis, and intestinal bleeding with eventual mortality within 10–15 days postirradiation [5]. Recently, it was shown that Lgr5+ stem cells were more sensitive to X-ray radiation than others in intestine and markedly reduced 24 h after irradiation [6]. In the present investigation, we observed a similar phenomenon using heavy ion irradiation