2003 – NETRIN-1 REJUVENATES THE AGED HEMATOPOIETIC STEM CELL NICHE BY RESTORING THE DNA DAMAGE RESPONSE.

Abstract

Stem cells reside in specialized tissue-specific microenvironments termed ‘niches’ wherein they receive instructive signals to preserve their regenerative potential. Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell function. However, the causes underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness during aging, remain unclear. Here, we sought to determine whether functional deficits within aged blood stem cells can be restored by rejuvenating their supportive niche cells- endothelial cells and Leptin Receptor+ mesenchymal stromal cells- within the bone marrow microenvironment. We identify Netrin-1 as a critical regulator of bone marrow niche cell fitness during homeostasis, regeneration, and aging. Niche -specific deletions of Netrin-1 induces premature aging of their bone marrow 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 loss of niche-derived Netrin-1 results in accumulation of DNA damage within the bone marrow niche and blood stem cells. We identify that DDR downregulation and DNA damage accumulation represent conserved attributes of an aged bone marrow microenvironment. We show that Netrin-1 supplementation is sufficient to reactivate DDR, resolve DNA damage, and restore functional potential of the aged bone marrow niche and blood stem cells. Lastly, we demonstrate that Netrin-1 mediated niche rejuvenation is sufficient to restore the regenerative capacity of an aged hematopoietic system to endure serial chemotherapy regimens. Stem cells reside in specialized tissue-specific microenvironments termed ‘niches’ wherein they receive instructive signals to preserve their regenerative potential. Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell function. However, the causes underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness during aging, remain unclear. Here, we sought to determine whether functional deficits within aged blood stem cells can be restored by rejuvenating their supportive niche cells- endothelial cells and Leptin Receptor+ mesenchymal stromal cells- within the bone marrow microenvironment. We identify Netrin-1 as a critical regulator of bone marrow niche cell fitness during homeostasis, regeneration, and aging. Niche -specific deletions of Netrin-1 induces premature aging of their bone marrow 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 loss of niche-derived Netrin-1 results in accumulation of DNA damage within the bone marrow niche and blood stem cells. We identify that DDR downregulation and DNA damage accumulation represent conserved attributes of an aged bone marrow microenvironment. We show that Netrin-1 supplementation is sufficient to reactivate DDR, resolve DNA damage, and restore functional potential of the aged bone marrow niche and blood stem cells. Lastly, we demonstrate that Netrin-1 mediated niche rejuvenation is sufficient to restore the regenerative capacity of an aged hematopoietic system to endure serial chemotherapy regimens.