Netrin-1 Upregulation Restores Bone Marrow Niche Cells to Rejuvenate Aspects of Hematopoiesis
To what degree is the age-related decline in activity of important stem cell populations driven by intrinsic damage versus changes in the surrounding cells of the stem cell niche? Stem cells require the support of the niche, and there is evidence to suggest that the better studied types of stem cell (muscle, hematopoietic, neural) are more affected by the cell environment than by any damage to the stem cells themselves. Even so, it is quite clear that stem cells do suffer nuclear DNA mutations, as evidenced by the existence of somatic mosaicism. In that context, the research here is interesting: researchers find a way to regulate the behavior of the bone marrow hematopoietic niche that rejuvenates some measures of hematopoiesis in old mice.
Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels.
We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.