mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance.
mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance.
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DOI：
10.1016/j.stem.2017.11.008
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发表时间：
2017-12-07
期刊：
影响因子：
23.9
通讯作者：
Jasper H
中科院分区：
文献类型：
--
作者：
Haller S;Kapuria S;Riley RR;O'Leary MN;Schreiber KH;Andersen JK;Melov S;Que J;Rando TA;Rock J;Kennedy BK;Rodgers JT;Jasper H
自我更新和分化之间的平衡确保再生上皮组织中干细胞（SC）池的长期维持。这种平衡在高再生压力时期受到挑战，并且在老年动物中经常受到损害。在这里，我们发现TOR信号是反复再生过程中SC损失的关键调节因子。在再生刺激下，果蝇肠上皮和小鼠气管上皮中的SCs表现出短暂的TOR信号激活。尽管这种激活是SC在损伤反应中快速增殖所必需的，但反复的损伤会导致SC损失。一致地，小鼠气管和肌肉中与年龄相关的SC损失可以分别通过药物或基因抑制mTORC1信号传导来预防。这些发现强调了TOR信号在SC功能中的进化保守作用，并确定了mTORC1的反复激活是与年龄相关的SC衰退的驱动因素。通过对果蝇和小鼠的研究，Jasper和他的同事证明，由于生长调节剂mTORC1在SC激活过程中的短暂激活，反复的再生事件会导致组织干细胞（SCs）的损失。药理抑制mTORC1可以防止这种损失，并限制SC数量的年龄相关性下降。
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here we show that TOR signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition of mTORC1 signaling, respectively. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline. Studying flies and mice, Jasper and colleagues demonstrate that repeated regenerative episodes results in the loss of tissue stem cells (SCs) due to the transient activation of the growth regulator mTORC1 during SC activation. Pharmacological inhibition of mTORC1 can prevent this loss and limit the age-related decline in SC numbers.
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DOI：
10.1083/jcb.201103018
发表时间：
2011-05-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Amcheslavsky A;Ito N;Jiang J;Ip YT
通讯作者：
Ip YT
影响因子：
4.5
作者：
Biteau B;Karpac J;Supoyo S;Degennaro M;Lehmann R;Jasper H
通讯作者：
Jasper H
DOI：
10.1073/pnas.0809144106
发表时间：
2009-01-27
影响因子：
11.1
作者：
Hsu, Hwei-Jan;Drummond-Barbosa, Daniela
通讯作者：
Drummond-Barbosa, Daniela
影响因子：
21.3
作者：
Jones, D. Leanne;Rando, Thomas A.
通讯作者：
Rando, Thomas A.
影响因子：
29
作者：
Jasper H;Jones DL
通讯作者：
Jones DL