Project description
Microenvironmental determinants of cell fate commitment in the mammalian haematopoietic system
The molecular mechanisms underlying cell fate commitment in the mammalian haematopoietic system are poorly understood. The EU-funded ImmuNiche project aims to understand the cell type composition of the mouse bone marrow using single-cell RNA sequencing and high-resolution spatial analysis of gene expression in tissue sections. Using this approach, the project team will examine the co-localisation of haematopoietic cells and other bone marrow cell types and predict niches of haematopoietic progenitors that reveal microenvironmental determinants of haematopoietic cell fate. The project will investigate the pathogenesis of myelodysplastic syndromes (MDS) that give rise to leukaemia with a poor prognosis. The conserved niche regulators of cell fate commitment involved in disease pathogenesis will be established and functionally analysed in murine models of MDS.
Objective
The complex architecture of the mammalian hematopoietic system has been studied for decades, yet the molecular mechanisms underlying cell fate commitment remain poorly understood. Although cytokine signals are major determinants of hematopoietic cell fate, only few niches of stem and progenitor cells have been characterized. Here, we propose to resolve the cell type composition of mouse bone marrow by integrating single-cell RNA-seq with high-resolution spatial analysis of gene expression in tissue sections, visualizing ~250 cell type specific markers by multiplexed single-molecule RNA fluorescent in situ hybridization. This approach will reveal preferential co-localization of hematopoietic cells with other bone marrow-resident cell types, and globally predict niches of hematopoietic progenitor sub-types to pinpoint microenvrionmental determinants of hematopoietic cell fate. Based on this reference we will investigate the role of the microenvironment in the pathogenesis of myelodysplastic syndromes (MDS), representing one of the most frequent blood cell malignancies, commonly giving rise to leukaemia with poor prognosis. To investigate conservation of microenvironmental determinants of normal and malignant hematopoietic differentiation in human, we will apply the same strategy to healthy donors and human MDS patients and compare predicted cell types, differentiation trajectories, and niche interactions to those derived from healthy mice and murine MDS models. This approach will reveal conserved niche regulators of cell fate commitment involved in disease pathogenesis, which we will functionally analyse in murine models to identify novel therapeutic targets for prevention and treatment of MDS. Our approach represents a blueprint for investigating human malignancies of under-characterized tissues by applying cutting-edge high-resolution techniques in combination with advanced computational methods to jointly analyse the murine model and human patient microenvironment.
Fields of science
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
97070 Wuerzburg
Germany