FOR 2033:  The Hematopoietic Niches

• Subject Area: Medicine
• Term: since 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232863826

Somatic stem cells are critical to maintain highly regenerative tissues such as the skin, the gastro-intestinal mucosa and the blood system. These systems are characterized by the presence of a hierarchy of tissue-specific cells which are embedded in a network of supportive cells of mesenchymal origin, the so-called niche. Hematopoietic stem cells (HSC) are probably the best understood somatic stem cells and their transplantable activity is being used on a day-to-day basis for clinical regenerative therapies. The niche is not a passive player in hematopoiesis. Rather, it is pivotal for the control of the balance between HSC self-renewal and differentiation as well as the of control HSC dormancy and proliferation. Despite the important role of the hematopoietic niche in health and disease, our knowledge of its biology is still limited. The niche environment comprises various cell types characterized by a growing number of markers which are part of the bone marrow HSC niches. Although the precise composition of the quiescent HSC niche is still a matter of debate, research is starting to focus on the signals that the different cell types transmit to regulate HSC function. During the previous funding period the research Unit has reported progress in the description of niche cell types, the mediators niche cells produce, and the molecular mechanisms of how these influence HSC behavior. The Research Unit showed that the niche plays a particularly important role to maintain stem cell numbers in times of stress, such as during infections, after irradiation or myelo-ablative therapy, regeneration of the blood cell system after wounding or transplantation and in in vitro cultures. Detailed studies to unravel the precise cellular and molecular interactions within the individual components of the niche and in HSCs will allow to counteract the loss of stem cells usually noted under these conditions. In the second funding period of this research unit we will build on our previous results to address the following major issues:• What are the key cellular and molecular factors of the niche which act across species, and control self-renewal and HSC quiescence during steady state and hematopoietic stress?• What are the key signaling pathways which determine niche composition and leukemia-associated niche remodeling?• How does the niche, including the extracellular matrix, respond to leukemic cells, and which of those responses promote survival and progression of leukemia?The project: NicHem consortium will unravel the complex and dynamic HSC-niche interactions that are active during homeostasis, stress and disease by combining advanced imaging methods with genetics, gene-editing tools, next-generation sequencing, and molecular technologies. Insights from these studies will not only serve as a model for many other somatic stem cells but will also help to better understand and possibly treat various hematological diseases.

• DFG Programme: Research Units

Projects

• Cellular and molecular components of a functional niche for human and mouse hematopoietic stem cells. (Applicant Waskow, Claudia )
• Characterisation of the PKC-beta-NF-kB signalling pathways activated in the bone marrow niche of chronic lymphocytic leukaemia (Applicant Ringshausen, Ingo )
• Coordination Funds (Applicant Oostendorp, Robert A.J. )
• Dissecting Lymphoma Niche Interactions (Applicant Schmidt-Supprian, Marc )
• Dissecting the interaction of the PIM1/CXCR4 axis and Hedgehog signaling within the niche determing HSC mobilization and leukemic transformation (Applicants Dierks, Christine ;  Duyster, Justus )
• Exploration of the role of neural-type receptors and the ECM proteins SPARC and Tenascin C in the bone marrow HSC-niche unit (Applicants Nowak, Daniel ;  Trumpp, Ph.D., Andreas )
• In vivo analysis of hematopoietic stem/progenitor cell interaction with the niche (Applicant Massberg, Steffen )
• Role of Secreted frizzled-related Protein 1 (Sfrp 1) in the function of the hematopoietic niche (Applicant Oostendorp, Robert A.J. )
• The bone marrow niche under inflammatory stress (Applicant Essers, Marieke )

• Spokesperson: Professor Dr. Robert A.J. Oostendorp