The Aged Bone Marrow Niche Impedes Hematopoietic Stem Cell Function

Stem cell activity declines with age for a variety of reasons. Damage in the stem cells, damage in the supporting cells of the stem cell niche, as well as altered behavior in stem cells and niche cells, a reaction to signaling changes such as increased inflammation. In some populations, such as muscle stem cells, the evidence suggests that reactions to signaling are a much more important factor than intrinsic damage. Those stem cells can in principle be put back to work in an aged individual. For hematopoietic stem cells, responsible for generating blood and the immune system, the evidence is less clear. In very late life it has been shown that these cells are very damaged, but it remains to be determined as to whether the majority of the problem is damage or reactions to signaling in earlier old age.

Given this, more research such as the work noted here is needed to better understand the aging of this vital stem cell population and its niche. The nature of this age-related decline determines which approaches to rejuvenation are more likely to work. The data here suggest that delivering new, replacement hematopoietic stem cells will be impeded by changes and damage in the aged stem cell niche. The niche is a sufficiently important determinant of function to require attention.

Aged bone marrow niche impedes function of rejuvenated hematopoietic stem cells

A new study shows that the youthful function of rejuvenated HSCs upon transplantation depends in part on a young bone marrow "niche," which is the microenvironment surrounding stem cells that interacts with them to regulate their fate. "The information revealed by our study tells us that the influence of this niche needs to be considered in approaches to rejuvenate old HSCs for treating aging-associated leukemia or immune remodeling."

Old HSCs exhibit a reduced reconstitution potential and other negative aspects such as altered gene expression profiles and an increase in a polar distribution of proteins. (Polarity is believed to be particularly important to fate decisions on stem cell division and for maintaining an HSC's interaction with its niche. Consequently, a failure to establish or regulate stem cell polarity might result in disease or tissue deterioration.) Aging of HSCs might even affect lifespan. Researchers already knew that increased activity of a protein called Cdc42, which controls cell division, leads to HSC aging, and that when old HSCs are treated ex vivo with CASIN, an inhibitor of Cdc42 activity, they stay rejuvenated upon transplantation into young recipients. The aim of this latest study was to learn what happens to these rejuvenated HSCs when they are transplanted into an aged niche.

Researchers transplanted rejuvenated aged HSCs into three groups of mice: young (8 to 10 weeks old), old (19 to 24 months old) and young cytokine osteopontin (OPN) knockout mice (8 to 12 weeks old). The team had recently demonstrated that a decrease in the level of secreted OPN in the aged bone marrow niche confers hallmarks of aging on young HSCs, and also that secreted OPN regulates HSC polarity. Old HSC and rejuvenated old HSCs were therefore transplanted into the OPN knockout recipients to test whether a lack of this protein in the niche affects the function of old rejuvenated HSCs. The results were then analyzed for up to 23 weeks after transplantation."They showed us that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of OPN found in aged niches. This tells us that in order to sustain the function of rejuvenated aged HSCs, we will likely need to address the influence of an aged niche on rejuvenated HSCs."

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.

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