Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response

Pradeep Ramalingam, Michael C. Gutkin, Michael G. Poulos, Taylor Tillery, Chelsea Doughty, Agatha Winiarski, Ana G. Freire, Shahin Rafii, David Redmond and Jason M. Butler ()
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Pradeep Ramalingam: University of Florida Health Cancer Center
Michael C. Gutkin: Hackensack University Medical Center
Michael G. Poulos: University of Florida Health Cancer Center
Taylor Tillery: Hackensack University Medical Center
Chelsea Doughty: Hackensack University Medical Center
Agatha Winiarski: University of Florida Health Cancer Center
Ana G. Freire: Hackensack University Medical Center
Shahin Rafii: Department of Medicine, Weill Cornell Medicine
David Redmond: Department of Medicine, Weill Cornell Medicine
Jason M. Butler: University of Florida Health Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37783-4

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