LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity.
LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity.
复制标题
Lgr5+肠干细胞表现出性别依赖性的放射敏感性。
作者：
组织放射敏感性在放射治疗的总体结果中起着关键作用。识别预测患者如何对放射治疗作出反应的特征，使临床医生能够最大限度地扩大治疗窗口。有限的临床数据表明男性和女性放疗结果存在差异。由于肠道对放射毒性的敏感性，胃肠道恶性肿瘤的放射治疗仍然是一个挑战。在这份手稿中，我们证明了性别特异性差异的肠上皮细胞的放射敏感性。在小鼠模型的腹部照射，我们观察到一个显着增加的氧化应激和损伤的男性相比，女性。来自雄性小鼠的Lgr5+ve肠干细胞对辐射诱导的毒性表现出更高的敏感性。然而，肠道放射敏感性的性别特异性差异并不依赖于性激素，因为我们在青春期前小鼠中证明了类似的性别特异性放射敏感性差异。在离体研究中，我们发现与女性相比，来自男性的患者来源的肠类器官（PID）显示出对辐射的更高敏感性，这从出芽隐窝、类器官大小和膜完整性的损失中可以看出。人类LGR 5+肠干细胞的转录组学分析表明，与女性相比，男性中辐射诱导的线粒体氧化代谢上调，这是辐射敏感性差异的可能机制。
Tissue radiosensitivity plays a critical role in the overall outcome of radiation therapy. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data have suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In a mouse model of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity were not dependent on sex hormones, as we demonstrated similar sex-specific radiosensitivity differences in pre-pubescent mice. In an ex vivo study, we found that patient-derived intestinal organoid (PID) from males showed higher sensitivity to radiation compared to females as evident from loss of budding crypts, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation-induced upregulation of mitochondrial oxidative metabolism in males compared to females, a possible mechanism for radiosensitivity differences.
登录
查看更多内容
影响因子：
5.2
作者：
Chmielewski-Stivers N;Petit B;Ollivier J;Monceau V;Tsoutsou P;Quintela Pousa A;Lin X;Limoli C;Vozenin MC
通讯作者：
Vozenin MC
影响因子：
3.6
作者：
Baskar R;Lee KA;Yeo R;Yeoh KW
通讯作者：
Yeoh KW
影响因子：
23.9
作者：
Metcalfe, Ciara;Kljavin, Noelyn M.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
3.9
作者：
Heath, JP
通讯作者：
Heath, JP
影响因子：
64.8
作者：
Ayyaz, Arshad;Kumar, Sandeep;Gregorieff, Alex
通讯作者：
Gregorieff, Alex