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

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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.