Somatic stemcells are critical to maintain highly regenerative tissue such as the skin, the gastro-intestinal mucosa and the blood system. Hematopoietic stem cells (HSCs) are well understood somatic cells, which have been used successfully for clinical regenerative therapies. HSCs are located in the bone marrow, although the importance of their microenvironment, the so called niche has only recently been recognized. Despite the important role of hematopoietic niche, our knowledge of its biology is limited. The niche environment comprises various cell types, like osteoblasts, multipotent and perivascular stromal cells, as well as macrophages. FOR 2033 investigates the following:
Part A: Our previous work and and investigations of the other groups showed that dysregulation of the niche awakes HSCs from quiescence. the definite cellular mechanism, controlling the balance of quiencence and activation are still unclear. Thus, we address the following issues:
- Identification of the cellular components regulating HSCs like mesenchymal subpopulations, mature bloodcells, under steady state and stress conditions
- Characterization of interaction of various celltypes regulating migration and localization of HSCs
Part B: Only very little is known about the molecular mechanisms regulating HSC self-renewal and activation. It was described that malignant leukemia-inducing cells target the niche, which protects against current therapies, although the mechanisms involved remain unclear. Detailed knowledge of niche signalling pathways involved in HSC-regulation could contribute to succsessful therapies against leukemia. Therefore, we address the following issues:
- Identification of niche signalling pathways which regulate HSC self-renewal or quiescence.
- Determination of niche signals required for protection of leukemic stem cells (LICs)
- Determination how leukemic cells disturb the niche (basic resarch via mouse models as well as samples of patients suffering from leukemia)
In summary, FOR 2033 will combine advanced imaging methods with genetics and molecular technologies to unraval the complex dynamic of HSC-niche interaction. Insights from the HSC-niche field will not only serve as a model for many other less advanced somatic stem cells but will also help to better understand and possibly treat various hematological diseases.