Department of Medicine, University of Florida Health Cancer Center, Gainesville, FL, USA.
Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, 07110, USA.
Nat Commun. 2023 Apr 10;14(1):2018. doi: 10.1038/s41467-023-37783-4.
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.
衰老相关缺陷会影响干细胞支持性龛位，导致干细胞活性的年龄相关性下降。然而，与年龄相关的龛位缺陷的机制，以及恢复龛位功能是否能提高干细胞适应性，仍然不清楚。在这里，我们试图确定通过在骨髓（BM）中恢复其支持性龛位是否可以恢复衰老的血液干细胞功能。我们确定 Netrin-1 是 BM 龛细胞衰老的关键调节因子。龛位特异性缺失 Netrin-1 会在 BM 微环境中引起过早衰老表型，而在老年小鼠中补充 Netrin-1 会使衰老的龛位细胞年轻化，并恢复衰老血液干细胞的竞争适应性，使其达到年轻水平。我们表明 Netrin-1 在维持活跃的 DNA 损伤反应（DDR）中起着至关重要的作用，并且龛位中源自 Netrin-1 的衰老相关下降导致 BM 微环境中的 DNA 损伤积累。我们表明，补充 Netrin-1 足以解决 DNA 损伤，并恢复衰老的 BM 龛位和血液干细胞的再生潜能，使其能够耐受连续的化疗方案。
