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

造血干细胞（HSC）是未分化的细胞，经过很长一段时间的自我更新，产生具有补充整个血液系统能力的造血祖细胞（HPC）。由于不受控制的扩张和失去HSC都是致命的，因此需要严格控制自我更新还是分化的决定。有充分的证据表明，造血干细胞的生态位和不对称细胞分裂都参与控制造血干细胞的自我更新或分化。在这种情况下，我们最近发现了四种在HSC/HPC分裂中经常不对称分离的蛋白质。值得注意的是，其中三种蛋白，四跨蛋白CD53和CD63，以及转铁蛋白受体是内核体相关蛋白。这一观察结果与最近在模式生物中的发现相结合，即内体机制的组成部分参与细胞命运规范过程，例如通过处理Notch信号通路的组成部分，表明内体腔室与控制HSC和HPC自我更新与分化的决定机制之间存在联系。基于这些观察结果，我们决定研究内体腔室在人HSC/HPC细胞命运规范过程中的作用。因此，我们的目的是研究通过过表达或rnai介导的功能丧失实验或药物介导的内吞作用抑制后，对HSC/HPC的生物学影响。

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.