Cellular senescence is one of the causes of aging. Lingering senescent cells produce the senescence-associated secretory phenotype, a damaging mix of secreted molecules that generate inflammation and tissue dysfunction. However, senescence is also an early defense against cancerous cells, especially those that gain the embryonic-like ability to replicate without limit and spawn many different cell types. Such cells are near all shut down and destroyed by the senescence process, at least in the earlier stages of life. Further, cellular senescence is also involved in tissue repair in a different, transient way. Wounds spur the temporary creation of senescent cells, which appear important in the coordination of healing.
Reprogramming normal cells into induced pluripotent stem cells is an important part of modern stem cell research, a basis for future regenerative therapies, and a potential way to produce arbitrary patient matched cell types to order. Yet it is in essence quite similar to the damage and mutation that produces rampaging cancer cells, freed from their restrictions. It also has more than a passing relation to the activities that take place during regeneration. Given this, we might not be too surprised to find links between cellular senescence and induced pluripotency. The paper here outlines some of these connections, and they are most interesting. This will probably have implications for a range of future efforts to control cellular activity in the body. For instance, inducing pluripotency in living animals has been tried, and at least in the short term shown to be beneficial - the contents of this paper put a novel spin on the sort of cautions that line of research might inspire.
Senescence is a cellular response to damage characterized by a stable cell cycle arrest and by the secretion of cytokines and other soluble factors with pleiotropic functions, collectively known as senescence-associated secretory phenotype or SASP. The primary role of senescence is thought to be the orchestration of tissue remodeling and repair. This has been demonstrated in a variety of settings, including tissue repair in the skin and liver. In general, senescent cells are efficiently cleared as part of a successful tissue repair process. However, upon severe or chronic damage, senescence-orchestrated tissue repair may fail and senescent cells may accumulate, contributing to disease and aging.
The power of cellular senescence in inducing tissue remodelling has been further extended to processes of cellular reprogramming in vivo. The transgenic expression of the four transcription factors abbreviated as OSKM (Oct4, Sox2, Klf4, and c-Myc) in adult mice induces dedifferentiation and cellular reprogramming within multiple tissues. However, in addition to reprogramming, the activation of OSKM also results in cellular damage and senescence. Therefore, OSKM induces two opposite cellular fates, namely senescence and reprogramming, that coexist in vivo in separate, but proximal, subsets of cells. Importantly, it has been demonstrated that senescence plays an active role in facilitating in vivo reprogramming through the paracrine action of the SASP, with interleukin-6 (IL6) as a critical mediator. Of note, IL6 plays an important role also during in vitro reprogramming. Moreover, the concept that senescence promotes cellular plasticity has been further extended to the activation of somatic stem/progenitor cells. In particular, the SASP can confer somatic stem/progenitor features onto proximal epithelial cells in several tissues.
The tumor suppressor genes p53, p21, Ink4a, and Arf act as cell-autonomous barriers for cellular reprogramming. These barriers are conceivably activated by cellular damages associated to reprogramming, most notably replication stress, which result in proliferation arrest and, consequently, inhibit reprogramming. At the same time, p53 and the genetic locus Ink4a/Arf also affect reprogramming, although in opposite directions, through cell extrinsic mechanisms. In the absence of p53, the induction of OSKM leads to exacerbated damage and senescence in tissues, which results in high levels of IL6 that further enhance reprogramming. The Ink4a/Arf locus plays a complex role in reprogramming: it promotes reprogramming through the paracrine influence of senescence, and, at the same time, it is a cell-autonomous barrier for reprogramming. In vivo, the absence of Ink4a/Arf severely impairs OSKM-senescence, IL6 levels are modestly increased, and reprogramming is very inefficient. Therefore, the positive cell-autonomous impact of Ink4a/Arf deficiency is completely obscured in vivo by the absence of senescence and IL6 secretion. The emerging picture is that tissue damage and senescence provide a tissue microenvironment that is critical for OSKM reprogramming in vivo.