Project Details
Projekt
Role of macrophage-derived ApoE in the stem cell-ness and differentiation of hematopoietic stem cells
Applicant
Professorin Dr. Elvira Mass
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 533863915
Hematopoietic stem cells (HSCs) arise and mature at various anatomical sites during embryogenesis, such as the fetal liver, before they seed the adult bone marrow (BM). The fetal liver provides a critical niche for the expansion and differentiation of hematopoietic stem and progenitor cells (HPSCs), essential for fetal growth and development. This supportive environment is rich in growth factors and cytokines. As development progresses, the BM becomes the primary site of hematopoiesis, housing a dynamic environment composed of various cell types that interact with HSCs to regulate their function. These interactions are vital for maintaining long-term (LT)-HSC dormancy, self-renewal, and differentiation into various blood cell lineages. HSC fate relies on the metabolic state and the presence of metabolic intermediates that act as signaling molecules. Quiescent HSCs predominantly rely on glycolysis, supporting a low metabolic state and minimizing the production of reactive oxygen species (ROS). In contrast, HSCs that exit quiescence shift towards oxidative phosphorylation to meet increased energy demands. This shift is accompanied by higher ROS levels, which, if excessive, can induce DNA damage and accelerate HSC ageing. Therefore, regulating mitochondrial dynamics and ROS production is crucial for HSC function and longevity. Despite recent studies showing that macrophages contribute to the HSC niche, the precise nature of LT-HSC and macrophage interactions in the developing liver and BM, and whether macrophages directly influence LT-HSC proliferation and differentiation, need further investigation. Further, previous work demonstrates that apolipoprotein E (ApoE) and its receptors are crucial for understanding how diet-induced metabolic and inflammatory states influence hematopoiesis. However, it remains to be investigated how ApoE regulates HSC metabolism during development and steady-state conditions. Since macrophages are the major producers of ApoE, this proposal aims to characterize the fetal liver HSC niche and the postnatal BM niche, and decipher the role of macrophage-derived ApoE in HSC proliferation and differentiation. By investigating these interactions, we aim to gain a comprehensive understanding of the mechanisms regulating HSC function and their implications for hematopoiesis throughout life.
DFG Programme
Research Units
