Self-renewal versus differentiation in hematopoietic stem and progenitor cells: a focus on asymmetric cell divisions.

Like other somatic stem cells, hematopoietic stem cells (HSC) have the ability to either self-renew or to differentiate. They are essentially required for the hematopoietic homeostasis. In this context HSC do not only need to replenish peripheral blood cells of all lineages, but also have to keep their pool relatively constant. Since disruption of the underlying control mechanisms can lead to degeneration or expansion of the HSC-pool as it occurs after irradiation or in leukemia, it is an important concern to unveil mechanisms that govern the decision of self-renewal versus differentiation in HSC-biology. There is good evidence that certain extrinsic cues provided in a special environment, the HSC-niches, essentially take part in regulating the HSC-pool in vivo and might also be involved in leukemogenesis. Apart from that, asymmetric cell divisions seem to be another control instance in hematopoietic homeostasis. It has been shown that siblings of primitive hematopoietic cells often adopt different cell fates, and very recently we identified four proteins that segregate asymmetrically in a proportion of dividing primitive hematopoietic cells. Whether asymmetric cell division participates in leukemogenesis, remains to be investigated. However, on the example of neural stem cells of the Drosophila larvae, the neuroblasts, asymmetrically segregating molecules have been identified, i.e. the tumor suppressor protein Brat and the transcription factor Prospero, that are required to suppress self-renewal in one of the arising daughter cells and whose loss of function results in tumor formation. These findings provide an attractive model of how defects in the process of asymmetric cell divisions might transform normal HSC/HPC into leukemic cells.