The impact of human aged bone marrow niche on human hematopoietic stem cell function

In humans, aging of the hematopoietic system is associated with anaemia, impaired immune responses and increased frequency of myeloid malignancies. The hematopoietic system is maintained by hematopoietic stem cells (HSCs).

HSCs reside in the bone marrow (BM) within specialized niches, where they self-renew and differentiate to produce all blood and immune cells.

In the clinical setting of BM transplantation, HSCs from older donors result in a reduced transplantation success, with a worse level of engraftment and higher overall mortality. This demonstrates that there is a reduction in the function of aged human HSCs (hHSCs). Causes of this impaired hHSC function with age still remain unclear.

Therefore, it is of great importance to uncover and subsequently target factors that contribute to hHSC aging in order to attenuate impaired haematopoiesis in the elderly.

Due to the lack of meaningful human BM (hBM) niche models in the aging field, the current understanding of how extrinsic changes (stemming from the aged hBM niche) contribute to the aging of hHSC is far less advanced compared to the knowledge of the contribution of cell-intrinsic changes.

Thus, this proposal focuses on providing a significant understanding of age-associated changes within the hBM niche and their contribution to the aging of hHSCs using an aging-centred hBM niche model.

Transplantation of young BM hHSCs into this advanced niche model revealed that an aged hBM niche confers aging on young hHSCs.

To this end, the target of the proposal is to address the following questions:(i)How does aging affect the cellular and molecular composition of the hBM niche?(ii)To which extent does an aged hBM niche affect aging of hHSCs?(iii)What are the underlying mechanisms that confer an age-like function on hHSCs?MANAGE HSC addresses both technological and conceptual challenges in studying the role of the hBM niche in regulating hHSC function in the context of normal hematopoiesis and aging.