Cellular senescence has been recognized as a central mechanism blocking tumor initiation and progression. Cells enter a senescent state as a response to different stresses which entails an irreversible growth arrest, as well as changes in cell metabolism and morphology. Despite the importance of this tumor suppressive mechanism, the function and the fate of the senescent cells in the living tissue are poorly understood.
In order to study the characteristics of senescent cells, their eventual fate, and their effect on different cellular compartments within normal and cancerous tissues, we have developed a novel system that allows induction of cellular senescence in vivo. We have generated transgenic mice carrying a central mediator of the senescence response – the human p14ARF. This allows controlled activation of p14ARF in various tissues. We found that p14ARF activation in the skin leads to p53 activation and accumulation of senescent cells in this tissue. Once generated, senescent cells remain in the tissue for periods of weeks, even when the initiating signal is turned off. We examined the influence of senescent cell accumulation on various components of the skin. Interestingly, we found that stem cells in the skin are more susceptible to senescence than differentiated cells, and induction of senescence in the stem cell niche, leads to irreversible stem cell dysfunction. Our findings provide basic insights into the mechanisms of senescence induction in vivo and the influence of this program on the normal function and structure of the skin.
