Hormetic endoplasmic reticulum stress in hematopoietic stem cells.
Hormetic endoplasmic reticulum stress in hematopoietic stem cells.
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DOI：
10.1097/moh.0000000000000668
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发表时间：
2021-11-01
影响因子：
3.2
通讯作者：
Luchsinger LL
中科院分区：
文献类型：
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作者：
Luchsinger LL
造血干细胞(HSCs)具有在极端的细胞增殖和环境压力下终生再生的能力。然而，控制造血干细胞再生特性的机制仍然难以捉摸。内质网应激已成为支持HSC自我更新和多能性的重要信号事件。本综述的目的是总结内质网应激在HSCs中作为细胞保护作用的途径。最近的研究表明，在健康的HSC中，多个未折叠蛋白反应(UPR)的信号级联被持续激活，这表明低剂量的内质网应激是HSCs的一个特征。应激适应是细胞和生物体的细胞保护和寿命的一个特征，也就是众所周知的兴奋作用。然而，将这些信息整合成有用的知识以改善HSCs的治疗用途仍然具有挑战性，HSCs所需的内质网应激诱导的上游激活子和下游转录程序仍有待发现。HSCs的维持需要对内质网应激反应进行剂量依赖的模拟，其中包括持续的、低剂量的UPR。解开这个信号节点的复杂性可能会阐明与HSCs再生相关的机制，可以利用这些机制来扩大HSCs用于细胞治疗、体外和体内移植。
Hematopoietic stem cells (HSCs) possess the ability to regenerate over a lifetime in the face of extreme cellular proliferation and environmental stress. Yet, mechanisms that control the regenerative properties of HSCs remains elusive. ER stress has emerged as an important signaling event that supports HSC self-renewal and multipotency. The purpose of this review is to summarize the pathways implicating ER stress as cytoprotective in HSCs. Recent studies have shown multiple signaling cascades of the unfolded protein response (UPR) are persistently activated in healthy HSCs, suggesting that low-dose ER stress is a feature HSCs. Stress adaptation is a feature ascribed to cytoprotection and longevity of cells as well as organisms, in what is known as hormesis. However, assembling this information into useful knowledge to improve the therapeutic use of HSCs remains challenging and the upstream activators and downstream transcriptional programs induced by ER stress that are required in HSCs remain to be discovered. The maintenance of HSCs requires a dose-dependent simulation of ER stress responses that involves persistent, low-dose UPR. Unraveling the complexity of this signaling node may elucidate mechanisms related to regeneration of HSCs that can be harnessed to expand HSCs for cellular therapeutics ex vivo and transplantation in vivo.