mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration
mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration
复制标题
mTOR 信号传导通过平衡毛发再生过程中 BMP 介导的抑制来促进干细胞活化
DOI：
10.1093/jmcb/mjv005
复制
发表时间：
2015-02-01
影响因子：
5.5
通讯作者：
Duan, Enkui
中科院分区：
文献类型：
--
作者：
Deng, Zhili;Lei, Xiaohua;Duan, Enkui
毛囊（HF）经历退化（退化期）、休止期（休止期）和再生（生长期）阶段的循环。毛发生长期开始时，毛囊干细胞（HFSC）获得足够的激活线索，以克服抑制信号，主要是BMP途径，从他们的利基细胞。在这里，我们揭示了mTOR复合物1（mTORC 1）信号在HFSC中被激活，这与HFSC在休止期到生长期过渡时的激活相一致。通过使用诱导型条件性基因靶向策略和药理学抑制方法在生长期开始之前消融或抑制成人皮肤上皮中的mTOR信号传导，我们证明了不能对mTOR信号传导作出响应的HF显示出显著延迟的HFSC激活和延长的休止期。出乎意料的是，BMP信号传导活性在mTOR信号传导缺陷的HF中显著延长。通过体外功能获得和丧失研究，我们发现mTORC 1信号对BMP信号产生负面影响，BMP信号是mTORC 1信号促进HFSC激活的主要机制。事实上，在体内抑制BMP的拮抗剂头蛋白拯救HFSC激活缺陷mTORC 1-null皮肤。我们的研究结果揭示了mTOR信号在调节干细胞活化中的关键作用，通过平衡毛发再生过程中BMP介导的抑制。
Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals, mainly the BMP pathway, from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration.