Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults,STEM CELLS

当前位置： X-MOL 学术 › STEM CELLS › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults
STEM CELLS ( IF 4.0 ) Pub Date : 2020-12-03 , DOI: 10.1002/stem.3313
Zenghua Lin _{1,

2} , Maile K Hollinger ₁ , Zhijie Wu ₁ , Wanling Sun _{1,

3} , Kaylind Batey ₁ , Jisoo Kim ₁ , Jichun Chen ₁ , Xingmin Feng ₁ , Neal S Young ₁

Affiliation

The role of mammalian target of rapamycin and its suppressor sirolimus in the regulation of hematopoietic stem and progenitor cells (HSPCs) is controversial. We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin⁻CD150⁺ bone marrow cells from sirolimus‐treated TBI mice had increased expression of c‐Kit and other hematopoietic genes. HSPCs from sirolimus‐treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased γ‐H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post‐radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5‐fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c‐Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34⁺ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.

中文翻译：

西罗莫司在造血损伤后增强造血干细胞和祖细胞再生

哺乳动物雷帕霉素靶点及其抑制因子西罗莫司在造血干细胞和祖细胞 (HSPC) 调控中的作用存在争议。我们在这里展示了西罗莫司增强了暴露于亚致死全身照射 (TBI) 和其他再生应激源的小鼠 HSPC 的再生。排序林⁻ CD150 ⁺来自西罗莫司治疗的 TBI 小鼠的骨髓细胞增加了 c-Kit 和其他造血基因的表达。当通过体内竞争性移植测试时，来自西罗莫司治疗的 TBI 小鼠的 HSPC 在功能上是有能力的。用西罗莫司治疗的小鼠中 HSPC 的辐射后再生伴随着流式细胞术检测到的 γ-H2AX 水平降低和定量聚合酶链反应 DNA 修复基因的表达增加。西罗莫司对辐射后细胞死亡和 DNA 损伤的减少与 HSPC 中细胞活性氧 (ROS) 的清除率增强有关。在注射了血毒剂、白消安和 5-氟尿嘧啶的小鼠中，也观察到西罗莫司的 HSPC 恢复增加。相比之下，西罗莫司在稳定状态下对正常小鼠的 HSPC 没有影响，但在 c-Kit 基因座携带 Wv 突变的小鼠中刺激了 HSPC 扩增。在人对小鼠的异种移植中，西罗莫司增强了受照射的人 CD34 的植入⁺细胞。总之，我们的结果与西罗莫司对造血应激反应加速 HSPC 恢复一致，与减少的 DNA 损伤和 ROS 相关。西罗莫司可能具有治疗和预防造血损伤的临床应用。

更新日期：2021-01-28

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11