Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells.
Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells.
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DOI：
10.1016/j.stem.2018.08.019
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发表时间：
2018-10-04
期刊：
影响因子：
23.9
通讯作者：
Rando TA
中科院分区：
文献类型：
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作者：
Liu L;Charville GW;Cheung TH;Yoo B;Santos PJ;Schroeder M;Rando TA
随着年龄的增长，组织再生能力下降与干细胞功能受损有关。然而，对于衰老过程中干细胞功能的治疗调节，可用的策略有限。以骨骼肌干细胞(MuSCs)为模型系统，我们确定有丝分裂突变导致的细胞死亡是老年动物干细胞增殖受损的原因之一。有丝分裂细胞的死亡是由于微环境中Notch激活剂的缺乏所致。我们发现，在正常的肌肉再生过程中，配体依赖的Notch刺激通过抑制MDM2的表达来激活MuSCs中的P53，而这一途径在老年动物中受到了损害。P53的药理激活促进了衰老的MuSCs在体内的扩张。综上所述，这些发现阐明了Notch-P53信号轴在MUSC激活期间的存活中发挥着重要作用，并且在衰老过程中受到失调，导致了肌肉再生潜力的年龄相关性下降。老年动物的骨骼肌干细胞在激活后发生有丝分裂突变，导致细胞死亡，限制了其在肌肉再生过程中的存活和自我更新。MUSC有丝分裂灾难受Notch-P53轴调控。P53水平的药理增强促进了老年MuSCs的存活。
The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Taken together, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and that is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential. Skeletal muscle stem cells (MuSCs) in aged animals exhibit higher incidence of cell death via mitotic catastrophe upon activation, limiting their survival and self-renewal during muscle regeneration. MuSC mitotic catastrophe is regulated by a Notch-p53 axis. Pharmacologic enhancement of p53 levels promotes the survival of aged MuSCs.
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影响因子：
5.8
作者：
Ianzini F;Bertoldo A;Kosmacek EA;Phillips SL;Mackey MA
通讯作者：
Mackey MA
影响因子：
11.8
作者：
Conboy, IM;Rando, TA
通讯作者：
Rando, TA
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
DOI：
10.1073/pnas.0409130102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Huang, XX;Tran, T;Zhang, PM
通讯作者：
Zhang, PM
影响因子：
8
作者：
通讯作者：
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