The aim of our research is the identification of cell-autonomous and -extrinsic factors supporting the life-long function of hematopoietic stem cells and their differentiation products: mature blood cells: immune cells. This includes the understanding of stem-, progenitor-, and immune-cell homeostasis, e.g. their generation and turn-over during steady-state and under inflammatory (infection) conditions in young adults and during the aging process. The research of my laboratory, thus, focuses on uncovering basic mechanisms that regulate immune cell biology in the young and elderly, and this understanding may pioneer novel translational approaches.
Stem cell maintenance is essential for continuous tissue formation during steady-state and under stress. The constant supply of de novo generated mature cells from adult stem cells is pivotal for the lifelong function of many organs, in particular for tissues with high turn-over rates including blood. Understanding the mechanisms of fate choice in stem and progenitor cells holds the promise of replacement of non-functioning tissues by engineered tissues in the future. One of the most thoroughly studied adult stem cell types are hematopoietic stem cells that give rise to all blood cells. HSC can be prospectively isolated to very high purity, and after bone marrow transplantation the infused donor HSCs disclose their amazing regenerative potential and continuously generate blood cells over long periods of time in the recipients. Despite the precise phenotypic description of HSCs the molecular mechanisms, including signaling pathways and receptor interplay, underlying fate-choice decisions are not resolved, and failure of hematopoiesis can lead to life-threatening blood disorders disclosing the need for a tight regulation of fate choices of HSC to ensure welfare of the organism. We focus on cell-intrinsic and extrinsic niche-mediated signals that regulate hematopoietic stem and progenitor cell fate.
We recently have added another layer of complexity to control mechanisms regulating the size of immune cell populations and have shown that the pool size of important antigen-presenting cells (dendritic cells) in the adult mouse strictly depends on the presence of hematopoietic cells of embryonic origin. Embryo-derived specialized tissue-resident macrophages, that can be targeted using a newly developed lineage tracer mouse tool generated by our lab, are crucial for the generation and regeneration of dendritic cells in situ. We further could show that bone-resorbing osteoclasts are of embryonic origin and that their regeneration occurs via the fusion of blood monocytes with pre-existing embryo-derived osteoclasts in vivo. We have a particular interest in understanding the differential roles of embryonic versus adult macrophages in inflammatory processes in the context of xenotransplantation and sepsis. Of course, we strive to translate our findings to the human setting taking advantage of our self-generated humanized mouse models.