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Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline
2018-07-03

From: https://www.nature.com/articles/s41467-018-06353-4


Ageing of stem cells has been considered as the underlying cause for ageing of tissues and organs, especially in a biological system that is characterized by a high turnover such as haematopoiesis1,2. In humans, anaemia, decreased competence of the adaptive immune system, an expansion of myeloid cells at the expense of lymphopoiesis, and a higher frequency of haematologic malignancies have been reported to be hallmarks of ageing3,4,5.


The age-associated phenotypes are initiated at the very top of the haematopoietic hierarchy, i.e., in the haematopoietic stem and progenitor cells (HPCs)2,6. With age, the HPC population undergo both quantitative (e.g., an increase in number) and functional changes (e.g., a decreased ability to repopulate the bone marrow3,4,7,8). Transcriptomic studies have provided a blueprint of the underlying molecular mechanisms and indicated that genes associated with cell cycle, myeloid lineage specification, as well as with myeloid malignancies were up-regulated in old HPCs, when compared to young ones5,9,10. The aforementioned knowledge on the various mechanistic aspects of HPC ageing was mostly, if not exclusively, gained by studies in murine models of ageing and has yet to be validated in human subjects.


Additionally, changes in the HPC microenvironment—the bone marrow niche—also influence haematological ageing. Whereas alterations in adhesion molecules, which are expressed in the cellular niche, and which are essential for homing and maintenance of HPCs, have been described, how they vary with the ageing process has not been defined11,12,13,14,15,16. In previous studies, we demonstrated specific transcriptomics and epigenetic alterations characteristic for ageing of human mesenchymal stem/stromal cells (MSCs)17,18, while other groups indicated that different cellular elements in the marrow such as monocytes and macrophages could also play major roles19,20,21. Whereas these various mechanisms of ageing have been studied in a few, individual cell populations constituting the bone marrow, our understanding of the roles of intrinsic mechanisms, i.e., in the HPCs, vs. extrinsic ones, such as in the marrow niche, has remained fragmented.


The overarching goal of this study is therefore to acquire a systems understanding of the molecular mechanisms involved in ageing of human HPCs, as well as those in the cell populations comprising the marrow niche. As cell functions are more directly characterized by their proteins than their transcript complements, we performed a comprehensive and quantitative proteomics analysis of the HPCs and their niche in a large cohort of human subjects from different age groups. The underlying datasets should represent not only a valuable resource for mechanistic analyses and for validation of knowledge gained from animal models, but also provide an atlas of proteomic signatures of human ageing processes within the cellular network of the bone marrow. The systemic data should build a foundation for a better understanding of age-related diseases such as myelodysplastic syndromes (MDS) in the future.


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