In the skin, however, the mTOR-dependent persistent proliferation of epithelial cells within the HF in response to Wnt1, or the direct activation of mTOR in HF stem cells, may result in the exhaustion of the HF stem cells compartment. In this scenario, excessive proliferation and activation of mTOR in stem cells may increase their turnover, prematurely exhausting the ability of these stem cells to repopulate the hair follicle. Consistent with this, pharmacological inhibition of mTOR with rapamycin was sufficient to prevent stem cell ablation upon Wnt1 expression, as reflected the maintenance of the population of CD34[SUP]+[/SUP] bulge stem cells. mTOR inhibition also impaired the acquisition of a premature senescence phenotype caused by Wnt1 expression in mice and by the exposure of CD34[SUP]+[/SUP] cells to Wnt, thus raising the possibility that mTOR may contribute to OIS when triggered by the aberrant activity of other oncogenes, an area that will warrant further investigation.
The emerging picture from our study and recent published reports is that Wnt1 may promote the proliferation and regenerative capacity of tissue-specific stem cells (
Katoh and Katoh, 2007), and that mTOR may play a key role as part of the growth promoting pathway by which Wnt acts (
Inoki et al., 2006). Long term activation of Wnt, however, may cause cell senescence and the exhaustion or demise of the stem cell compartment by the persistent activation of mTOR. While the exhaustion of the stem cells may act as a protective mechanism against oncogenic perturbation of this particular self-renewing cell population, the persistent activation of mTOR may also contribute to accelerating aging, hence providing a novel molecular target for pharmacological intervention in multiple diseases that are characterized by the pathological depletion of stem cells, loss of tissue regenerative capacity, and tissue aging.
