Smurf2 regulates hematopoietic stem cell self-renewal and aging.
Smurf2 regulates hematopoietic stem cell self-renewal and aging.
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SMURF2调节造血干细胞自我更新和衰老。
DOI：
10.1111/acel.12195
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发表时间：
2014-06
期刊：
影响因子：
7.8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Ramkumar C;Kong Y;Trabucco SE;Gerstein RM;Zhang H
干细胞自我更新能力的年龄依赖性下降在衰老中起着关键作用，但这种下降背后的确切机制尚不清楚。通过限制增殖能力，衰老被认为在干细胞自我更新的年龄依赖性下降中起重要作用，尽管支持这一假设的直接证据在很大程度上缺乏。我们以前已经确定E3泛素连接酶Smurf2作为衰老的关键调节因子。在这项研究中，我们发现Smurf2缺陷的小鼠在正常稳态条件下骨髓中有一个扩增的造血干细胞（HSC）区室，这种扩增与HSC的增殖增强和静止减少有关。令人惊讶的是，Smurf 2缺陷小鼠中HSC循环增加和静止减少并没有导致干细胞过早耗尽。相反，老年Smurf2缺陷小鼠中的HSC比老年野生型HSC具有更好的再增殖能力，这表明HSC功能随年龄的下降是Smurf2依赖的。此外，Smurf2缺陷型HSC在连续移植中表现出提高的长期自我更新能力和减少的衰竭。由于我们发现Smurf2的表达随着年龄的增长而增加，并在连续移植过程中对再生应激作出反应，我们的研究结果表明Smurf2在调节HSC自我更新和衰老中起着重要作用。
The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence. In this study, we found that mice deficient in Smurf2 had an expanded hematopoietic stem cell (HSC) compartment in bone marrow under normal homeostatic conditions, and this expansion was associated with enhanced proliferation and reduced quiescence of HSCs. Surprisingly, increased cycling and reduced quiescence of HSCs in Smurf2-deficient mice did not lead to premature exhaustion of stem cells. Instead, HSCs in aged Smurf2-deficient mice had a significantly better repopulating capacity than aged wild-type HSCs, suggesting that decline in HSC function with age is Smurf2 dependent. Furthermore, Smurf2-deficient HSCs exhibited elevated long-term self-renewal capacity and diminished exhaustion in serial transplantation. As we found that the expression of Smurf2 was increased with age and in response to regenerative stress during serial transplantation, our findings suggest that Smurf2 plays an important role in regulating HSC self-renewal and aging.
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影响因子：
23.9
作者：
Liu Y;Elf SE;Miyata Y;Sashida G;Liu Y;Huang G;Di Giandomenico S;Lee JM;Deblasio A;Menendez S;Antipin J;Reva B;Koff A;Nimer SD
通讯作者：
Nimer SD
影响因子：
5.2
作者：
Papathanasiou, Peter;Attema, Joanne L.;Karsunky, Holger;Xu, Jian;Smale, Stephen T.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
64.8
作者：
Molofsky, Anna V.;Slutsky, Shalom G.;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
影响因子：
10.5
作者：
Maier, B;Gluba, W;Scrable, H
通讯作者：
Scrable, H
影响因子：
8
作者：
Attema, J. L.;Pronk, C. J. H.;Bryder, D.
通讯作者：
Bryder, D.