Interactions between the hematopoietic system and the bone marrow microenvironment in aging

1 PhD project offered in the IPP summer call Molecular Biomedicine & Ageing

Scientific Background

Throughout life, a finely regulated balance between quiescence and activation allows the hematopoietic stem cell (HSC) to continuously replenish all mature blood cells in homeostasis and in response to challenges. However, in aging HSCs become dysfunctional and show differentiation imbalances toward an increased production of myeloid cells at the expense of the adaptive immune lymphocytes. This has been associated with an increased risk of age-related conditions including cardiovascular complications, impaired immune responses, and myeloid premalignancies. The changes in aging HSCs result not only from accumulation of cell intrinsic insults but also from cell extrinsic effects. Within the bone marrow (BM), HSCs interact with several cellular and matrix (growth factors, extracellular vesicles) components which are crucial in the regulation and maintenance of HSC fate. While it has been shown that aged HSC can be partially rejuvenated once exposed to a young BM microenvironment, it is not clear which environmental cues contribute to the aging of the hematopoietic system. Proteases of the coagulation system have been implicated in the regulation of HSC fate (extravascular coagulation signaling) in homeostatic condition as well as in aging mouse models. Characterization of these interaction could provide new approaches to counteract or delay age-associated exhaustion of HSC.

PhD Project: Impact of intercellular interaction within the bone marrow microenvironment on hematopoiesis during aging

The aim of the project is to determine the contribution of interactions within the BM microenvironment (e.g. mesenchymal stromal cells and endothelial cells) to disrupted HSC function and unbalanced hematopoiesis in aging. Ultimately, the long-term goal will be to identify targets for the development of rejuvenation strategies. The work of the PhD candidate will include the interrogation of single cell sequencing datasets (established in the host lab) of young and old hematopoietic progenitors in different mouse models with an accelerated aging phenotype. This will lead to the identification followed by validation, via application of state-of-the-art BM imaging an functional assays, of possible regulators of age-associated reprogramming. Furthermore, different mouse models with accelerated senescence in stromal cells will be employed to address the impact of the BM microenvironment on aging of HSC. Characterization of the senescent associated secretory phenotype BM environment (e.g. of extracellular vesicles) may also be required to identify underlying molecular mechanisms for altered interaction that affects HSC output in aging. 

A sound knowledge in molecular and cell biology and/or protein chemistry and an interest in working with animal models are expected for successful candidates. The candidate should have an interest in systems biology approaches and develop skills to apply bioinformatics on newly generated and available omics data sets for further validation in in vivo models of aging. This will be an interactive project involving different research groups which provide a variety of learning opportunities and interdisciplinary approaches.

If you are interested in this project, please select Ruf as your group preference in the IPP application platform.


Publications relevant to this project

Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W (2019) Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol 4(39). Link

Gur-Cohen S, Itkin T, Chakrabarty S, Graf C at al Ruf W and Lapidot T (2015) PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nature Medicine 21(11): 1307-1317. Link

Muller-Calleja N, Hollerbach A, Royce J, Ritter S et al Lackner KJ and Ruf W (2021) Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 371(6534). Link

Nguyen TS, Lapidot T and Ruf W (2018) Extravascular coagulation in hematopoietic stem and progenitor cell regulation. Blood 132(2): 123-131. Link

Woods K and Guezguez B (2021) Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia. Front Cell Dev Biol. 9:714716 Link

Pereira RS, Kumar R, Cais A, Paulini L, Kahler A, Bravo J, Minciacchi VR, Krack T, Kowarz E, Zanetti C, Godavarthy PS, Hoeller F, Llavona P, Stark T, Tascher G, Nowak D, Meduri E, Huntly BJP, Münch C, Pampaloni F, Marschalek R, Krause DS (2023) Distinct and targetable role of calcium-sensing receptor in leukaemia. Nat Commun. 14:6242. Link

Contact Details

Prof Wolfram Ruf
Website UMC
Website CHA