Stem Cells and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China.
South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China.
Theranostics. 2020 Aug 13;10(22):10171-10185. doi: 10.7150/thno.46415. eCollection 2020.
Acute gastrointestinal syndrome (AGS) is one of the most severe clinical manifestations after exposure to high doses of radiation, and is life-threatening in radiological emergency scenarios. However, an unmet challenge is lacking of an FDA-approved drug that can ameliorate the damage of radiation-exposed intestinal tissues and accelerate the regeneration of injured epithelia. In this study, we investigated whether the small molecule Me6TREN (Me6) can regulate intestinal stem cell (ISC) proliferation and promote crypt regeneration after irradiation. Lethally irradiated mice were administered with Me6 or PBS to study the survival rate, and sections of their small intestine were subjected to immunostaining to evaluate epithelial regeneration. An intestinal organoid culture system was employed to detect the role of Me6 in organoid growth and ISC proliferation. We further investigated the key signaling pathways associated with Me6 using microarray, western blotting, and RNA interference techniques. We identified the small molecule Me6 as a potent intestinal radiation countermeasure. Systemic administration of Me6 significantly improved ISC and crypt cell regeneration and enhanced the survival of mice after high doses of radiation. Using an intestinal organoid culture system, we found that Me6 not only induced ISC proliferation but also increased the budding rate of intestinal organoids under unirradiated and irradiated conditions. Me6 remarkably activated the expression of ISC-associated and proliferation-promoting genes, such as , , and . Mechanistically, Me6 strongly stimulated the phosphorylation of β-catenin at the S552 site and increased the transcriptional activity of β-catenin, a key signaling pathway for ISC self-renewal and proliferation. This is further evidenced by the fact that knockdown of β-catenin abolished the effect of Me6 on intestinal organoid growth and crypt regeneration in irradiated mice. The small molecule Me6TREN induced ISC proliferation, enhanced intestinal organoid growth , and promoted intestinal tissue regeneration after radiation injury by activating β-catenin signaling.
急性胃肠综合征（AGS）是暴露于大剂量辐射后最严重的临床症状之一，在放射应急情况下危及生命。然而，目前仍缺乏一种经美国食品和药物管理局批准的药物，可以改善辐射暴露的肠组织损伤，并加速受损上皮的再生。在这项研究中，我们研究了小分子 Me6TREN（Me6）是否可以调节肠干细胞（ISC）增殖，并促进照射后隐窝的再生。用 Me6 或 PBS 处理致死性照射的小鼠，以研究存活率，并对其小肠切片进行免疫染色，以评估上皮再生。采用肠类器官培养系统来检测 Me6 在类器官生长和 ISC 增殖中的作用。我们进一步使用微阵列、Western blot 和 RNA 干扰技术研究了与 Me6 相关的关键信号通路。我们确定小分子 Me6 是一种有效的肠道辐射对策。全身给予 Me6 可显著改善 ISC 和隐窝细胞的再生，并提高高剂量辐射后小鼠的存活率。使用肠类器官培养系统，我们发现 Me6 不仅诱导 ISC 增殖，而且在未照射和照射条件下增加肠类器官的出芽率。Me6 显著激活了与 ISC 相关和促进增殖的基因的表达，如 、 、 和 。从机制上讲，Me6 强烈刺激β-catenin 在 S552 位点的磷酸化，并增加β-catenin 的转录活性，β-catenin 是 ISC 自我更新和增殖的关键信号通路。Me6 对辐射损伤后肠类器官生长和隐窝再生的影响被证实，即β-catenin 的敲低消除了 Me6 的作用。小分子 Me6TREN 通过激活β-catenin 信号，诱导 ISC 增殖，增强肠类器官生长 ，并促进辐射损伤后的肠组织再生。
