The role of the endosomal compartment in human hematopoietic stem and progenitor cell fate specification

内体区室在人类造血干细胞和祖细胞命运规范中的作用

• 批准号: 72414443
• 负责人: Professor Dr. Bernd Giebel
• 金额: --
• 依托单位: Institut für Transfusionsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/72414443?language=en
• 关键词: role; endosomal; compartment; human; hematopoietic

Hematopoietic stem cells (HSC) are undifferentiated cells, which self-renew over a long period of time and give rise to committed hematopoietic progenitor cells (HPC) containing the capability to replenish the whole blood system. Since both uncontrolled expansion as well as loss of HSC would be fatal, the decision of self-renewal versus differentiation needs to be tightly controlled. There is good evidence that both HSC niches as well as asymmetric cell divisions are involved in controlling whether HSC self-renew or become committed to differentiate. In this context, we recently identified four proteins which frequently segregate asymmetrically in dividing HSC/HPC. Remarkably, three of these proteins, the tetraspanins CD53 and CD63, and the transferrin receptor are endosome-associated proteins. This observation in conjunction with recent findings in model organisms that components of the endosomal machinery are involved in cell-fate specification processes, e.g. by processing components of the Notch signalling pathway, suggest a link between the endosomal compartment and the mechanisms governing the decision self-renewal versus differentiation of HSC and HPC.Based on these observations, we decided to investigate the role of the endosomal compartment in the cell-fate specification processes of human HSC/HPC. Therefore, we aim to study effects on the biology of HSC/HPC after manipulating essential components of the endosomal compartment by over-expression or RNAi-mediated loss-of-function experiments or after drug-mediated inhibition of endocytosis.

造血干细胞（HSC）是未分化的细胞，其在长时间内自我更新并产生含有补充整个血液系统的能力的定向造血祖细胞（HPC）。由于不受控制的扩张以及HSC的丧失都是致命的，因此需要严格控制自我更新与分化的决定。有很好的证据表明，HSC壁龛以及不对称细胞分裂都参与控制HSC自我更新或分化。在这种情况下，我们最近确定了四种蛋白质，经常分离不对称的分裂HSC/HPC。值得注意的是，其中三种蛋白质，四跨膜蛋白CD 53和CD 63以及转铁蛋白受体是核内体相关蛋白质。这一观察结果与最近在模式生物中发现的内体机制的组分参与细胞命运特化过程（例如通过加工Notch信号传导途径的组分）相结合，表明内体隔室与决定HSC和HPC的自我更新与分化的机制之间存在联系。我们决定研究内体区室在人HSC/HPC的细胞命运特化过程中的作用。因此，我们的目的是研究在通过过表达或RNAi介导的功能丧失实验或药物介导的内吞作用抑制后操纵内体区室的基本组分后对HSC/HPC生物学的影响。