Wnt-induced mTOR activation drives epidermal stem-cell senescence; rapamycin rescues it.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse |
| Journal | Cell stem cell |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.stem.2009.06.017 · PMID 19733540 · Free full text (PMC2939833) |
Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Although Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of beta-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation.
| Intervention | Wnt1 overexpression; rapamycin rescue |
| Target | mTOR |
| Model | Mouse (epidermal stem cells) |
| Effect | Wnt→mTOR drives stem-cell senescence/exhaustion and hair loss; rapamycin reverses it |