通过促进增殖,PERK信号维护了在内细胞网膜应激下造血干细胞池的完整性
Manxi Zheng1,2, Qinlu Peng1,2, Erin M Kropp3,4
1Hunan Key Laboratory of Animal Models and Molecular Medicine, School of Biomedical Sciences, Hunan University, Changsha, China.
Blood
|May 28, 2025
概括
蛋白质激酶R型内细胞网膜激酶 (PERK) 不是正常造血干细胞 (HSC) 功能必不可少的. 然而,在内质网膜应激下PERK的激活驱动HSC的过度增殖和枯竭,从而保持HSC池的完整性.
科学领域:
- 细胞生物学 细胞生物学
- 血液学 血液学 血液学
- 分子生物学分子生物学
背景情况:
- 造血干细胞 (HSC) 完整性依赖于自我更新和消除受损细胞.
- 展开的蛋白质反应 (UPR) 和其PERK通路与细胞应激反应有关.
- 在活体内PERK在HSC命运的确定在内质网膜 (ER) 压力下的作用尚不清楚.
研究的目的:
- 研究PERK在ER压力条件下调节HSC命运中的作用.
- 阐明PERK在ER压力期间影响HSC行为的机制.
主要方法:
- 使用ER相关降解 (ERAD) 组件 (Sel1L,Hrd1) 的淘汰模型来诱导ER压力.
- 评估了HSC的扩散,亡和自我更新能力.
- 分析了PERK激活,mTOR信号和活性氧物种水平.
主要成果:
- 对于稳定状态血液形成和高血小板自我更新,PERK是不可或缺的.
- 由ERAD中断引起的ER压力激活PERK,导致HSC的扩散和耗尽.
- PERK激活促进异常的mTOR信号传递和HSC超增殖,独立于亡.
- PERK 删除或酶死突变物拯救了 ERAD 缺陷引起的 HSC 缺陷.
结论:
- 珀克在消除压力高细胞中发挥着关键作用,通过一种增殖性,与亡无关的机制.
- 这种PERK介导的途径对于在ER压力下保持HSC池完整性至关重要.
- 揭示了PERK在HSC平衡中的新功能,超出了其已知的亲亡信号传递.
相关概念视频
01:01Regulation of Hematopoietic Stem Cells
3.3K
All blood and immune cells are produced from the multipotent hematopoietic stem cells (HSCs) by the process of hematopoiesis. However, they all have a limited life span. In addition, many are depleted in immune surveillance or combatting an injury or infection. This makes blood one of the most regenerative tissues. Hematopoiesis helps replenish these blood and immune cells, restoring the body's normal functioning. However, overproduction of blood and immune cells can make them cancerous or...
3.3K
01:19Multipotency of Hematopoietic Stem Cells
3.3K
The hematopoietic stem cells or HSCs are multipotent, meaning they can differentiate and give rise to all blood and immune cells. HSCs are maintained in the quiescent stage until an external stimulus initiates their differentiation. The multipotent HSCs exist as two heterogeneous populations, long-term repopulating cells (LTRC) and short-term repopulating cells (STRC). The two HSC populations have different surface markers or receptors and are classified based on quiescence and long-term...
3.3K
01:28Role of Hematopoietic Growth Factors
1.7K
Hematopoietic growth factors are molecules that regulate the differentiation rate of hematopoietic stem cells (HSCs). Erythropoietin (EPO), primarily produced by the kidneys, plays a crucial role in erythrocyte production. When oxygen levels in the blood are low, EPO is released into the bloodstream, reaching the bone marrow, where it stimulates HSCs to differentiate and mature into erythrocytes, which are vital for oxygen transport.
Thrombopoietin (TPO), mainly released by the liver,...
Thrombopoietin (TPO), mainly released by the liver,...
1.7K
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
2.3K
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.3K
01:31Regulation of the Unfolded Protein Response
2.6K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K
01:14Maintenance of the ES Cell State
2.3K
The cells of the blastocyst inner cell mass only remain pluripotent for a short time. This state of pluripotency and self-renewal can be maintained in embryonic stem (ES) cell culture by adding specific chemicals or growth factors to ensure the cells can continue dividing and later differentiate into different cell types. In some cases, the cells are grown on a feeder layer of differentiated cells, which provides the growth factors and extracellular matrix components necessary for stem cell...
2.3K