A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.
A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.
复制标题
DOI：
10.1371/journal.pone.0004934
复制
发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Blasco MA
中科院分区：
文献类型：
--
作者：
Flores I;Blasco MA
端粒的维持对于确保器官的适当大小和功能具有高周转率至关重要。特别是，侏儒表型以及与组织再生过早丧失相关的表型，包括皮肤（脱发、头发变灰、伤口愈合减少），在端粒酶（负责维持端粒长度的酶）缺陷的小鼠中发现。与这些表型的出现相一致，发现p53在这些小鼠的几种组织中被激活，其中被认为触发细胞衰老和/或凋亡反应。在这里，我们表明，p53废除拯救小尺寸表型和恢复端粒功能失调的端粒酶缺陷小鼠的表皮干细胞（ESC）的功能。特别是，p53消融恢复了促有丝分裂诱导后的毛发生长、皮肤更新和伤口愈合反应，以及挽救了体内ESC动员缺陷和体外ESC克隆形成活性缺陷。ESC功能的这种恢复伴随着衰老标志物的下调和端粒非常短的端粒缺陷小鼠的皮肤和肾脏中增殖的增加，而凋亡率没有变化。总之，这些发现表明存在p53依赖性衰老反应，作用于端粒功能失调的干/祖细胞，这积极限制了它们对组织再生的贡献，从而影响组织适应性。
Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing), are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC) of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.
登录
查看更多内容
影响因子：
11.4
作者：
Herrera, E;Samper, E;Blasco, MA
通讯作者：
Blasco, MA
影响因子：
56.9
作者：
Azzalin, Claus M.;Reichenbach, Patrick;Lingner, Joachim
通讯作者：
Lingner, Joachim
影响因子：
56.9
作者：
Herbig, U;Ferreira, M;Sedivy, JM
通讯作者：
Sedivy, JM
DOI：
10.1098/rstb.2003.1370
发表时间：
2004-01-29
影响因子：
6.3
作者：
Chan, SRWL;Blackburn, EH
通讯作者：
Blackburn, EH
影响因子：
50.3
作者：
Feldser, David M.;Greider, Carol W.
通讯作者：
Greider, Carol W.