Distinct Levels of Radioresistance in Lgr5(+) Colonic Epithelial Stem Cells versus Lgr5(+) Small Intestinal Stem Cells.
Distinct Levels of Radioresistance in Lgr5(+) Colonic Epithelial Stem Cells versus Lgr5(+) Small Intestinal Stem Cells.
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DOI：
10.1158/0008-5472.can-15-2870
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发表时间：
2017-04-15
期刊：
影响因子：
11.2
通讯作者：
Kolesnick R
中科院分区：
文献类型：
--
作者：
Hua G;Wang C;Pan Y;Zeng Z;Lee SG;Martin ML;Haimovitz-Friedman A;Fuks Z;Paty PB;Kolesnick R
虽然小肠和大肠拥有相似的Wnt驱动的富含亮氨酸重复序列的G蛋白偶联受体5(Lgr5)+成人上皮干细胞，但我们在这里报告了这两个器官对电离辐射的组织反应机制。利用Lgr5-LacZ转基因小鼠和Lgr5原位杂交，我们发现在体内结肠上皮干细胞(CESCs)比小肠隐窝基底部柱状干细胞(CBCs)对辐射的抵抗明显增强(D0=6.0±0.3Gyvs.1.3±0.1；p<；0.01)。因此，CESCs在30Gy射线照射后存活，而CBCs在15Gy后完全耗尽。EDU掺入研究表明，在19GY后，CBCs在12小时内退出生长停滞，恢复了正常的有丝分裂活性，尽管其中60%的细胞显示出残留的γH_2AX焦点，表明持续的未修复的DNA损伤。在完全DSB修复之前，检查点恢复是新定义的称为检查点适应的潜在致命性病理生理学的必要条件。在小肠粘膜中，检查点适应导致CBCs在辐射后48小时内高度致命性染色体异常和有丝分裂灾难的发生率增加8倍。相反，Lgr5+CESCs在19Gy后48h显示检查点恢复延迟，与完整的DSB修复和至少部分来源于存活CESCs的结肠粘膜再生相协调。小肠CBCs屈服于检查点适应的发现是第一次证明这种异常的细胞周期反应可能推动哺乳动物组织的辐射敏感性。
While small and large intestines possess seemingly similar Wnt-driven Leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5)+ adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. Employing Lgr5-lacZ transgenic mice and Lgr5 in situ hybridization, we found colonic epithelial stem cells (CESCs) markedly more radioresistant in vivo than small intestinal crypt base columnar stem cells (CBCs) (D0= 6.0±0.3 Gy vs. 1.3±0.1, respectively; p<0.01). Accordingly, CESCs survived 30 Gy exposure, while CBCs were completely depleted after 15 Gy. Edu incorporation studies indicated that after 19 Gy, CBCs exited growth arrest at 12 hours, resuming normal mitotic activity despite 60% of this population displaying residual γH2AX foci, indicative of persistent unrepaired DNA damage. Checkpoint recovery before complete DSB repair represents the sine qua non of a newly-defined potentially-lethal pathophysiology termed checkpoint adaptation. In the small intestinal mucosa, checkpoint adaptation resulted in CBCs succumbing to an eight-fold increase in incidence of highly-lethal chromosomal aberrations and mitotic catastrophe by 48 hours post-radiation. In contrast, Lgr5+ CESCs displayed delayed checkpoint recovery at 48 hours post-19 Gy, coordinated with complete DSB repair and regeneration of colonic mucosa originating, at least in part, from surviving CESCs. The discovery that small intestinal CBCs succumb to checkpoint adaptation is the first demonstration that this aberrant cell cycle response may drive mammalian tissue radiosensitivity.