Periodic Reporting for period 3 - ImmuNiche (Identifying spatial determinants of immune cell fate commitment)
Okres sprawozdawczy: 2022-10-01 do 2024-03-31
To understand the role of the microenvironment during hematopoiesis, spatial single-cell resolution analysis of bone marrow tissue would be required. To address this challenge within the ImmuNiche project, we are combining state-of-the-art single-cell RNA-sequencing technology with large-scale single-molecule resolution imaging of hundreds of genes in bone marrow tissue sections to create a single-cell resolution spatial map of the bone marrow . We are establishing tailored machine learning methods to integrate these data types and to infer cell-cell interactions and the underlying molecular pathways controlling blood cell differentiation. We will first investigate the bone marrow microenvironment in healthy mice as a model organism, and then apply the same approach to mouse models of myelodysplastic syndromes (MDS) and leukemia.
In parallel, we will collect bone marrow samples from MDS patients across different stages of the disease and perform a similar analysis on these samples to identify conserved disease-related changes of cell-cell interactions, which we prioritise as candidates for functional validation in the mouse model. With this strategy we hope to acquire a better understanding of the emergence of MDS and leukemia by elucidating the involvement of the microenvironment, and, in particular, to identify novel candidates for treating these malignancies.
As a major step towards our goal to study perturbation of the microenvironment during emergence of leukemia, we established a single-cell RNA-sequencing time course dataset of a leukemia mouse model. Finally, we were able to perform first single-cell RNA-sequencing pilot experiments on human patient bone marrow biopsies, and could recover a rich spectrum of cell types.
We expected to finalize establishment of our high-resolution spatial bone marrow imaging, which will enable us to go beyond previous spatial profiling attempts of bone marrow tissue. We will use this method in conjunction with the single-cell RNA-sequencing data, that we keep producing for the mouse model and human patient data, to gain unprecedented insights into the cellular architecture of the bone marrow niche in health and disease.