Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
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DOI：
10.1038/s41467-023-37783-4
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发表时间：
2023-04-10
影响因子：
16.6
通讯作者：
Butler, Jason M.
中科院分区：
文献类型：
--
作者：
Ramalingam, Pradeep;Gutkin, Michael C.;Poulos, Michael G.;Tillery, Taylor;Doughty, Chelsea;Winiarski, Agatha;Freire, Ana G.;Rafii, Shahin;Redmond, David;Butler, Jason M.
干细胞支持性小生境内的衰老相关缺陷导致干细胞活性的年龄相关性下降。然而，与年龄相关的生态位缺陷的潜在机制，以及恢复生态位功能是否可以改善干细胞适应性，仍然不清楚。在这里，我们试图确定老年造血干细胞功能是否可以通过恢复骨髓（BM）内的支持性小生境来恢复。我们确定Netrin-1作为BM龛细胞老化的关键调节因子。Netrin-1的小生境特异性缺失诱导BM微环境内的过早衰老表型，而用Netrin-1补充老年小鼠使老年小生境细胞恢复活力，并将老年造血干细胞的竞争适应性恢复到年轻水平。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，并且与衰老相关的小生境来源的Netrin-1的下降导致BM微环境中的DNA损伤积累。我们表明，Netrin-1补充剂足以解决DNA损伤并恢复老年BM龛和造血干细胞的再生潜力，以承受系列化疗方案。衰老与血液干细胞适应性的丧失有关，部分原因是干细胞支持性小生境的缺陷。在这里，作者证明，通过Netrin-1治疗恢复生态位功能能够使老化的血液干细胞恢复活力。
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. Aging is associated with a loss of blood stem cell fitness in part due to defects in stem cell-supportive niches. Here, the authors demonstrate that restoring niche function by treatment with Netrin-1 is able to rejuvenate aged blood stem cells.
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影响因子：
64.5
作者：
Bernitz, Jeffrey M.;Kim, Huen Suk;MacArthur, Ben;Sieburg, Hans;Moore, Kateri
通讯作者：
Moore, Kateri
影响因子：
5.3
作者：
Boyer NP;Gupton SL
通讯作者：
Gupton SL
DOI：
10.1016/j.bbmt.2016.11.007
发表时间：
2017-03
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
--
作者：
Rosko A;Artz A
通讯作者：
Artz A
影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut
影响因子：
64.5
作者：
Benedito, Rui;Roca, Cristina;Adams, Ralf H.
通讯作者：
Adams, Ralf H.