Projects Offered

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

Scientific Background

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

PhD Project: Contribution of cellular crosstalk within the bone marrow microenvironment to the aging of the hematopoietic system

The aim of the project is to dissect and identify the age-related changes in the BM microenvironment (e.g. megakaryocytes, mesenchymal stromal cells or endothelial cells) that contribute to the aging of the hematopoietic system. Ultimately, the long-term goal will be to identify targets for the development of rejuvenation strategies. We have established a large dataset of single cell whole transcriptomic analysis of hematopoietic progenitors and bulk RNAseq of endothelial cells from different mouse models with accelerated aging phenotype. The work of the PhD candidate will include data mining and integration of these datasets with resulting identification of candidate regulators of age-associated reprogramming. Validation of these candidates will be carried out through the employment of the various mouse models of accelerated senescence in stromal cells or accelerated aging of the hematopoietic system, available in the host lab. 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. This will be achieved via the implementation of state of the art multicolor flow cytometry analyses, imaging, omics techniques (e. g. single cell sequencing and proteomic). Theoretical and practical knowledge in molecular and cell biology and/or protein chemistry 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.

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

Contact Details

Prof Wolfram Ruf
Email
Website UMC