Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Periodic Report Summary 2 - SYSTEMAGE (Early warning signals of ageing in human stem cells and age-related disorders)

Project Context and Objectives:
The regenerative power of a living organism is linked to the potential of its stem cells to replace the corresponding damaged tissue.
Therefore organisms are as old as their stem cells. Whereas the vulnerability to cancer and chronic inflammation is associated with a decline of the immune system, the latter is in turn a sum product of interactions among hematopoietic stem cells (HSC), endothelial cells (EC) of the vascular systems and the microenvironment in the bone marrow, among others. Hence loss of regenerative function and propensity to contract cancers can be interpreted as harbingers of ageing at the level of somatic stem cells.
Using HSC and their microenvironment as a model, the principal goal of SyStemAge is to develop a systems-level understanding of the molecular mechanisms of ageing in somatic stem cells, the consequences and means to correct these age-related alterations and diseases.
Specifically, the missions of SyStemAge are:
1. To define the fundamental molecular and cell biological mechanisms of ageing in models of somatic stem cells, in order to comprehend the roles of genetic and proteomics alterations on the process of ageing.
2. To determine the molecular and cellular alterations of HSC and other cellular determinants that constitute the marrow niche (e.g. MSC, macrophages and lymphocytes) with ageing, and the impact of ageing of these cellular determinants on their respective supportive function for HSC.
3. To combine the cell biological, “-omics” and genetic studies to build models of age-related diseases such as myelodysplastic syndromes (MDS) and B-cell chronic lymphocytic leukaemia (B-CLL).
4. To translate the systems understanding of stem cell ageing into novel drug discovery strategies.

Project Results:
Work package 1 aims at defining the molecular players involved in the physiology of ageing in the human bone marrow of healthy individuals. For this purpose, different cell populations (HSC, MSC, macrophages/monocytes, lymphocytes, granulocytic and erythroid precursors) will be isolated and analysed using transcriptomics, proteomics and metabolomics. Within the second reporting period of the project, WP1 focuses on completing the collection of samples from healthy donors. The transcriptomic, proteomic and metabolomic analysis of the cellular material will be started. In addition, the co-culture system of HSC and SILAC-labeled MSC will be further optimized.
Work package 2 is aimed at complementing the work on human cells using animal models. During the second reporting period of the project, the analysis of hematopoietic stem cell (HSC) and endothelial cell (EC) aging, as well as the proposed animal models will be established and the analysis will be started. AF1 RNAi and AF1 overexpressing Drosophila as well as ATM-deficient mice will be generated and analyzed. Mice with YFP-labelled EC compartment and protocols for better Cre induction will be established. Rag2-/-Il2rg-/-KitW/Wv mouse strain will be utilized for forward fate mapping experiments. The protocols for lifespan assays, transcriptomic, epigenetic and metabolomic analyses will established and the analysis will be started. The transcriptome and methylome data of infant, young, mature and old lung EC will be generated and analyzed.
Work package 3 intends to define molecules and pathways that are deregulated in the age-related disorders MDS and B-CLL. During the second reporting period of the project, the protocols for sample acquisition and the processing pipelines will be finalized and the collection of cellular material will be completed. Transcriptomic, proteomic and metabolomic analysis will be in process.
Work package 4 aims at integrating all the data generated within the consortium with those available in the literature in order to generate computational models that will provide a global view of the processes involved in physiological HSC ageing, MDS and B-CLL. The main objectives during the reporting period will be the identification and molecular characterization of the physio-pathological processes related to HSC ageing and associated diseases (AX). In addition, the different cell types involved in these processes, and detailed in the project proposal, will be characterized in terms of presence/absence of genes and, where possible, their expression values. On the other hand, we will design and implement a strategy to build process-related networks, starting from the known genes involved and with the aim to maximize the information content of such networks, which will be later on converted into mathematical models. With the help of the consortium experts, we will characterize the physio-pathological processes associated to HSC ageing, B-CLL and MDS from a literature perspective.
Work package 5 aims to translate the knowledge gained in the other work packages into guiding principles for new therapeutic strategies and drug discovery. The main objectives during the reporting period will be the finalization of the set up of a 3D B-CLL/MSC spheroid co-culture system using different cell lines, and the use of this novel assay system for the screening of chemical compounds for the identification of potential drugs inhibiting B-CLL.

Potential Impact:
The systematic transcriptomics, proteomics and metabolomics experiments to be pursued within the SyStemAge consortium will yield important insights into the fundamental molecular mechanisms associated with physiological and pathological (MDS and B-CLL) human ageing processes. We expect to systematically characterize the molecular factors, signatures or the signalling routes specifically deregulated during the progression of MDS or B-CLL. Further expanding the study beyond these cell intrinsic factors, the SyStemAge consortium will conduct unique sets of experiments to monitor the impact of the environment on cellular senescence and provide a systematic survey of the interactions and early ageing signals taking place between the HSC and their environment, i.e. a variety of somatic stem cells that constitute the haematopoietic niche. The models we intend to generate are based on data essentially derived from human healthy donors or patients; they will directly be relevant to human biology. The SyStemAge consortium is committed to translate the cell biological, the “-omics” and the current knowledge into innovative strategies to treat age-related pathologies in human. The pursued computational and systems modelling experiments within the SyStemAge consortium will directly deliver series of tools and opportunities to detect, monitor and treat age-related diseases. The SyStemAge consortium activity will immediately contribute to bio-gerontology.

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Scientific Research
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