The bone marrow niche under inflammatory stress

• Applicant: Dr. Marieke Essers
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232863826

During homeostasis, hematopoietic stem cells (HSCs) are maintained in a state of quiescence and minorly contribute to steady-state hematopoiesis. In stress situations such as infection, chemotherapy, or transplantation, HSCs are forced to proliferate to rapidly regenerate compromised hematopoietic cells. Little is known about the processes which regulate stress-induced proliferation. We and others have shown that pro-inflammatory cytokines such as IFNa, produced in response to infection, can lead to the efficient activation of quiescent HSCs in vivo. In contrast, IFNa has the opposite effect in vitro, inhibiting HSC proliferation. This contrast between in vivo and in vitro effectsof pro-inflammatory cytokines suggests a role for the bone marrow niche in the response of HSCs to inflammatory stress. In the previous funding period, we demonstrated that IFNa induced activation of the stem cell compartment induces emergency megakaryopoiesis; that IFNa mediates remodelling of endothelial cells in the bone marrow niche; and that the ECM protein Matrillin 4 plays an important role in the response of HSCs to stress. In the coming funding period we plan to build on our successful previous work and extend our analysis of the response of bone marrow niche components respond to IFNa. We will not only continue our analysis of endothelial cells, but will also investigate the response of MSCs and osteoblasts in inflammation. Furthermore, in addition to inducing stress by treating with a single pro-inflammatory cytokine (IFNa), we will also induce a fullinfection using MCMV. In addition, by specifically deleting the receptor for IFNa in differentpopulations in the bone marrow by using cell-specific cre lines, we will investigate the importance of IFN signalling between HSCs and specific niche cells during inflammation. Finally, we will further investigate the critical role of the ECM in stress-induced activation of HSCs, by investigating the mechanism by which Matrillin 4 regulates HSCs. In summary, these data will help us to better understand how the bone marrow niche responds to inflammatory stress and how the different niche components and HSCs influence each other under these conditions.

• DFG Programme: Research Units
• Subproject of: FOR 2033: The Hematopoietic Niches