Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
Cell Stem Cell. 2017 Dec 7;21(6):806-818.e5. doi: 10.1016/j.stem.2017.11.008.
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 target of rapamycin (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, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. 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.
自我更新和分化之间的平衡确保了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，我们表明雷帕霉素靶蛋白（TOR）信号是 SC 在反复再生过程中丢失的关键调节剂。响应再生刺激，果蝇肠道上皮和小鼠气管上皮中的 SC 表现出 TOR 信号的短暂激活。尽管这种激活对于 SC 在损伤后快速增殖是必需的，但反复的损伤会导致 SC 丢失。一致地，通过药理学或遗传抑制哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号，可以分别预防小鼠气管和肌肉中的与年龄相关的 SC 丢失。这些发现突出了 TOR 信号在 SC 功能中的保守作用，并将反复的 mTORC1 激活确定为与年龄相关的 SC 衰退的驱动因素。
